Inhibitors of fatty acid amide hydrolase

ABSTRACT

Provided herein are compounds of formula (I): or pharmaceutically acceptable salts, solvates or prodrugs thereof or mixtures thereof, wherein Z 1 , Z 2 , X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , m and n are defined herein. Also provided are pharmaceutically acceptable compositions that include a compound of formula I and a pharmaceutically acceptable excipient. Also provided are methods for treating an FAAH-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the present invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national phase entry pursuant to 35 U.S.C. §371of International Application No. PCT/US2010/030276, which has theinternational filing date of Apr. 7, 2010, and which claims priority toU.S. Provisional Application Ser. No. 61/167,464, filed Apr. 7, 2009,all of which are incorporated herein by reference in their entireties.

BACKGROUND

Fatty acid amide hydrolase (FAAH), also referred to as oleamidehydrolase and anandamide amidohydrolase, is an integral membrane proteinthat degrades fatty acid primary amides and ethanolamides, includingoleamide and anandamide. FAAH degrades neuromodulating fatty acid amidesat their sites of action and is intimately involved in their regulation.

FAAH has been demonstrated to be involved in a number of biologicalprocesses and its inhibition has been shown to be effective in treatinga variety of conditions. For example, inhibiting FAAH has been shown tobe useful in treating chronic pain, acute pain, neuropathic pain,anxiety, depression, feeding behaviors, movement disorders, glaucoma,neuroprotection and cardiovascular disease.

SUMMARY

Compounds described herein, and pharmaceutically acceptable compositionsthereof, are effective inhibitors of fatty acid amide hydrolase (FAAH).

In one aspect, provided herein are compounds of formula I:

or pharmaceutically acceptable salts, solvates or prodrugs thereof, ormixtures thereof,

wherein:

is selected from a single bond and a double bond;

m is 1 when

is a single bond;

m is 0 when

is a double bond;

X¹ is selected from NR⁵ and CR⁶R⁷;

X² is selected from NR⁸ and CR⁹R¹⁰;

X³ is selected from NR¹¹ and CR¹²R¹³;

n is 0 or 1;

provided that at least one of X¹, X² and X³ is selected from NR⁵, NR⁸ orNR¹¹;

Z¹ is selected from —OR¹⁴ and C₁₋₆ alkyl;

Z² is selected from —OR¹⁵ and C₁₋₆ alkyl;

or alternatively, Z¹ and Z², together with the boron atom to which theyare bound, form a 5- to 8-membered ring having at least one O atomdirectly attached to the boron atom, wherein the ring is comprised ofcarbon atoms and optionally one or more additional heteroatomsindependently selected from the group consisting of N, S, and O, andwherein the ring is with 1-4 substituents selected from halogen, C₁₋₆alkyl, C₇₋₁₂ aralkyl, and oxo, and wherein the ring is optionally fusedto an phenyl ring;

R¹, R², R³, R⁴, R⁶, R⁷, R⁹, R¹⁰, R¹² and R¹³ each independently isselected from H, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆perhaloalkyl, —CN, —OR¹⁶, NR¹⁷R¹⁸, —C(O)R¹⁹, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, C₇₋₁₂ aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 memberedheteroaryl;

R⁵, R⁸ and R¹¹ each independently is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, —C(O)R²⁰, —C(O)OR²¹, —C(O)NR²²R²³, S(O)₂R²⁴,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered cycloheteroalkyl, 5-10membered heteroaryl, and —(CH₂)_(p)—R²⁵;

R¹⁴ and R¹⁵, at each occurrence, each independently is selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R¹⁶, at each occurrence, each independently is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;

R¹⁷ and R¹⁸, at each occurrence, each independently is selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R²⁶, —C(O)OR²⁷, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂ aralkyl, 3-10 membered cycloheteroalkyl,and 5-10 membered heteroaryl;

R¹⁹, at each occurrence, each independently is selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;

R²⁰ and R²¹ each independently is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedcycloheteroalkyl, 5-10 membered heteroaryl, and —(CH₂)_(q)—R²⁸;

R²² and R²³ each independently is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedcycloheteroalkyl, 5-10 membered heteroaryl, and —(CH₂)_(r)—R²⁹;

R²⁴ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered cycloheteroalkyl, 5-10 memberedheteroaryl, and —(CH₂)_(t)—R³⁰;

R²⁵ is selected from C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedcycloheteroalkyl, and 5-10 membered heteroaryl;

R²⁶ and R²⁷ each independently is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂ aralkyl,3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;

R²⁸, R²⁹, and R³⁰, at each occurrence, each independently is selectedfrom —OR³¹, —NR³²R³³, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedcycloheteroalkyl, and 5-10 membered heteroaryl;

R³¹, R³² and R³³, at each occurrence, each independently is selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, C₇₋₁₂ aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 memberedheteroaryl; and

p, q, r, and t, at each occurrence, each independently is selected from1, 2, 3, 4, 5 and 6.

In certain embodiments, the compound is of the formula III:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, the compound is of the formulae IIIa or IIIb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, the compound is of the formula VIII:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, the compound is of the formulae VIIIa or VIIIb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, the compound is of the formula VI:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, the compound is of the formulae VIa or VIb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, the compound of the formula IV:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, the compound is of the formulae IVa or IVb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, the compound is of the formula VII:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, the compound is of the formulae VIIa or VIIb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments,

is a double bond and m is 0.

In certain embodiments,

is a single bond and m is 1.

In certain embodiments, R¹ is H.

In certain embodiments, R² is H.

In certain embodiments, R³ is H and R⁴ is H.

In certain embodiments, Z¹ is —OR¹⁴ and Z² is —OR¹⁵. In certainembodiments, R¹⁴ is H and R¹⁵ is H (i.e., wherein Z¹ and Z² are both—OH).

In certain embodiments, X¹ is CR⁶R⁷. In certain embodiments, R⁶ is H andR⁷ is H.

In certain embodiments, X² is NR⁸. In certain embodiments, R⁸ isselected from C₁₋₆ alkyl, —C(O)R²⁰, —C(O)OR²¹, —C(O)NR²²R²³, S(O)₂R²⁴,and —(CH₂)_(p)—R²⁵.

In certain embodiments, R⁸ is —C(O)R²⁰, and R²⁰ is selected from C₁₋₆alkyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered cycloheteroalkyl,5-10 membered heteroaryl, and —(CH₂)_(q)—R²⁸. In certain embodiments,R²⁰ is (CH₂)_(q)—R²⁸, and R²⁸ is selected from C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl. Incertain embodiments, R²⁰ is (CH₂)_(q)—R²⁸, and R²⁸ is —NR³²R³³. Incertain embodiments, R³² and R³³ each independently is selected from H,C₁₋₆ alkyl, and C₇₋₁₂ aralkyl.

In certain embodiments, R⁸ is —C(O)OR²¹. In certain embodiments, R²¹ isselected from C₁₋₆ alkyl and —(CH₂)_(q)—R²⁸. In certain embodiments, R²⁸is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl.

In certain embodiments, R⁸ is —C(O)NR²²R²³. In certain embodiments, R²²and R²³ each independently is selected from H, C₁₋₆ alkyl, and—(CH₂)_(r)—R²⁹. In certain embodiments, R²⁹ is selected from C₆₋₁₀ aryland 5-10 membered heteroaryl.

In certain embodiments, R⁸ is —S(O)₂R²⁴. In certain embodiments, R²⁴ isselected from C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and—(CH₂)_(r)—R³⁹.

In certain embodiments, R⁸ is —(CH₂)_(p)—R²⁵. In certain embodiments,R²⁵ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl.

In certain embodiments, X¹ is CR⁶R⁷ and X² is NR⁸.

In certain embodiments, n is 1 and X³ is CR¹²R¹³. In certainembodiments, R¹² is H and R¹³ is H. However, in certain embodiments,there is no X³ (i.e., wherein n is 0).

In certain embodiments, the compound is selected from:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In another aspect, provided herein are pharmaceutical compositionscomprising a compound of the present invention or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, or mixture thereof, and apharmaceutically acceptable excipient.

In yet another aspect, provided herein are methods of treating anFAAH-mediated disorder comprising administering to a subject in needthereof a therapeutically effective amount of a compound of the presentinvention or a pharmaceutically acceptable salt, solvate or prodrugthereof, or mixture thereof, or a pharmaceutical composition thereof.

In certain embodiments, the FAAH-mediated disorder is selected from apainful disorder, an inflammatory disorder, an immune disorder,depression, anxiety, an anxiety-related disorder, a sleep disorder, afeeding behavior, a movement disorder, glaucoma, neuroprotection andcardiovascular disease.

In certain embodiments, the FAAH-mediated disorder is a painfuldisorder. In certain embodiments, the painful disorder is selected fromneuropathic pain, central pain, deafferentiation pain, chronic pain,stimulus of nociceptive receptors, acute pain, non-inflammatory pain,inflammatory pain, pain associated with cancer, preoperative pain,arthritic pain, lumbosacral pain, musculo-skeletal pain, headache,migraine, muscle ache, lower back and neck pain, and toothache. Incertain embodiments, the painful disorder is neuropathic pain. Incertain embodiments, the painful disorder is arthritic pain. In certainembodiments, the arthritic pain is osteoarthritic pain. In certainembodiments, the arthritic pain is rheumatoid arthritic pain. In certainembodiments, the inflammatory pain is associated with an inflammatorydisorder.

In certain embodiments, the FAAH-mediated disorder is an inflammatorydisorder. In certain embodiments, the inflammatory disorder is irritablebowel disease.

DETAILED DESCRIPTION

Provided are inhibitors of FAAH that contain at least one Lewis acidicboron head group, such as a boronic acid, boronic ester, borinic acid orborinic ester head group. Such compounds include compounds of formula Ior a pharmaceutically acceptable salt, solvate, or prodrug thereof, or amixture thereof:

wherein:

is selected from a single bond and a double bond;

m is 1 when

is a single bond;

m is 0 when

is a double bond;

X¹ is selected from NR⁵ and CR⁶R⁷;

X² is selected from NR⁸ and CR⁹R¹⁰;

X³ is selected from NR¹¹ and CR¹²R¹³;

n is 0 or 1;

provided that at least one of X¹, X² and X³ is selected from NR⁵, NR⁸ orNR¹¹;

Z¹ is selected from —OR¹⁴ and C₁₋₆ alkyl;

Z² is selected from —OR¹⁵ and C₁₋₆ alkyl;

or alternatively, Z¹ and Z², together with the boron atom to which theyare bound, form a 5- to 8-membered ring having at least one O atomdirectly attached to the boron atom, wherein the ring is comprised ofcarbon atoms and optionally one or more additional heteroatomsindependently selected from the group consisting of N, S, and O;

R¹, R², R³, R⁴, R⁶, R⁷, R⁹, R¹⁰, R¹² and R¹³ each independently isselected from H, halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆perhaloalkyl, —CN, —OR¹⁶, NR¹⁷R¹⁸, —C(O)R¹⁹, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, C₇₋₁₂ aralkyl, 3-10 membered heterocyclyl, and 5-10 memberedheteroaryl;

R⁵, R⁸ and R¹¹ each independently is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, —C(O)R²⁰, —C(O)OR²¹, —C(O)NR²²R²³, S(O)₂R²⁴,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl, and —(CH₂)_(p)—R²⁵;

R¹⁴ and R¹⁵, at each occurrence, each independently is selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R¹⁶, at each occurrence, each independently is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂aralkyl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;

R¹⁷ and R¹⁸, at each occurrence, each independently is selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R²⁶, —C(O)OR²⁷, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂ aralkyl, 3-10 membered heterocyclyl, and5-10 membered heteroaryl;

R¹⁹, at each occurrence, each independently is selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂aralkyl, 3-10 membered heterocyclyl, and 5-10 membered heteroaryl;

R²⁰ and R²¹ each independently is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, 5-10 membered heteroaryl, and —(CH₂)_(q)—R²⁸;

R²² and R²³ each independently is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, 5-10 membered heteroaryl, and —(CH₂)_(r)—R²⁹;

R²⁴ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl, and —(CH₂)_(t)—R³⁰;

R²⁵ is selected from C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, and 5-10 membered heteroaryl;

R²⁶ and R²⁷ each independently is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂ aralkyl,3-10 membered heterocyclyl, and 5-10 membered heteroaryl;

R²⁸, R²⁹, and R³⁰, at each occurrence, each independently is selectedfrom —OR³¹, —NR³²R³³, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, and 5-10 membered heteroaryl;

R³¹, R³² and R³³, at each occurrence, each independently is selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, C₇₋₁₂ aralkyl, 3-10 membered heterocyclyl, and 5-10 memberedheteroaryl; and

p, q, r, and t, at each occurrence, is independently selected from 1, 2,3, 4, 5 and 6.

In some embodiments, X² is NR⁸ and X¹ is CR⁶R⁷, i.e., compounds of theformula II:

or a pharmaceutically acceptable salt, solvate or prodrug thereof ormixture thereof, wherein

Z¹, Z², R¹, R², R³, R⁴, R⁶, R⁷, R⁸, X³, n and m are as defined above andherein. In certain preferred embodiments, Z¹ and Z² are both OH.

Embodiments of compounds of formula II include compounds of formula III(i.e., wherein n is 1 and X³ is CR¹²R¹³):

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein

Z¹, Z², R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R¹², R¹³ and m are as defined aboveand herein. In certain preferred embodiments, Z¹ and Z² are both OH.

Formula II also encompasses compounds of the formulae IIIa or IIIb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein Z¹, Z², R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R¹² and R¹³are as defined above and herein. In certain preferred embodiments, Z¹and Z² are both OH.

Other embodiments of compounds of formula II include compounds offormula IV (i.e., wherein n is 0):

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein

Z¹, Z², R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and m are as defined above andherein. In certain preferred embodiments, Z¹ and Z² are both OH.

Formula IV also encompasses compounds of the formulae IVa or IVb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein Z¹, Z², R¹, R², R³, R⁴, R⁶, R⁷, R⁸ and m are asdefined above and herein. In certain preferred embodiments, Z¹ and Z²are both OH.

In some embodiments of compounds having any of formulae II, III, IIIa,IIIb, IV, IVa, and IVb, R⁸ is not H. In certain embodiments, R⁸ is not—CH³. In certain embodiments, R⁸ is selected from C₁₋₆ alkyl, —C(O)R²⁰,—C(O)OR²¹, —C(O)NR²²R²³, S(O)₂R²⁴, and —(CH₂)_(p)—R²⁵.

In some embodiments wherein R⁸ is —C(O)R²⁰, R²⁰ is selected from C₁₋₆alkyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10membered heteroaryl, and —(CH₂)_(q)—R²⁸.

In some embodiments, wherein R⁸ is —C(O)R²⁰, R²⁰ is —(CH₂)_(q)—R²⁸, andR²⁸ is selected from C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, and 5-10 membered heteroaryl. In some embodiments, q is 1or 2 and R²⁸ is C₆₋₁₀ aryl or 5-10 membered heteroaryl. In someembodiments, q is 3 or 4 and R²⁸ is C₆₋₁₀ aryl or 5-10 memberedheteroaryl. In some embodiments, R²⁸ is phenyl. In other embodiments,R²⁸ is 5-10 membered heteroaryl (e.g., pyridyl, indolyl, benzofuranyl orbenzothiophenyl).

In some embodiments, wherein R⁸ is —C(O)R²⁰, R²⁰ is —(CH₂)_(q)—R²⁸, andR²⁸ is —NR³²R³³. In some embodiments, each of R³² and R³³ isindependently selected from H, C₁₋₆ alkyl, and C₇₋₁₂ aralkyl. In certainembodiments, q is 1 or 2. In certain embodiments, or q is 1. In someembodiments, one of R³² and R³³ is H and the other is C₁₋₆ alkyl orC₇₋₁₂ aralkyl (e.g., benzyl). In other embodiments each of R³² and R³³independently is C₁₋₆ alkyl or C₇₋₁₂ aralkyl (e.g., benzyl).

In some embodiments, R⁸ is —C(O)OR²¹ and R²¹ is selected from C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and —(CH₂)_(q)—R²⁸. Incertain embodiments, q is 1 or 2 and R²⁸ is selected from C₆₋₁₀ aryl and5-10 membered heteroaryl. In some embodiments, R²¹ is benzyl (i.e., q is1 and R²⁸ is phenyl).

In some embodiments, R⁸ is —C(O)NR²²R²³ and R²² and R²³ eachindependently is selected from H, C₁₋₆ alkyl, and —(CH₂)_(r)—R²⁹. Incertain embodiments, r is 1 or 2. In certain embodiments, r is 1. Insome embodiments, R²⁹ is C₆₋₁₀ aryl or 5-10 membered heteroaryl. In someembodiments, R²⁹ is phenyl. In some embodiments, one of R²² and R²³ is Hand the other is C₁₋₆ alkyl or —(CH₂)_(r)—R²⁹. In other embodiments,each of R²² and R²³ independently is C₁₋₆ alkyl or —(CH₂)_(r)—R²⁹. Insome embodiments, —(CH₂)_(r)—R²⁹ is benzyl (i.e., r is 1 and R²⁹ isphenyl).

In some embodiments, R⁸ is —S(O)₂R²⁴ and R²⁴ is selected from C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and —(CH₂)_(t)—R³⁹. Incertain embodiments, R²⁴ is phenyl.

In some embodiments, R⁸ is —(CH₂)_(p)—R²⁵ and R²⁵ is selected from C₆₋₁₀aryl and 5-10 membered heteroaryl. In some embodiments, p is 1 or 2. Incertain embodiments, p is 1. In certain embodiments, R²⁵ is phenyl. Inother embodiments, R²⁵ is 5-10 membered heteroaryl (e.g., pyridyl,indolyl, benzofuranyl or benzothiophenyl).

In some embodiments of compounds having any of formulae II, III, IIIa,IIIb, IV, IVa, and IVb, each of R³ and R⁴ is H or C₁₋₆ alkyl. In someembodiments, each of R³ and R⁴ is H.

In some embodiments of compounds having any of formulae II, III, IIIa,IIIb, IV, IVa, and IVb, each of R⁶ and R⁷ is H or C₁₋₆ alkyl. In someembodiments, each of R⁶ and R⁷ is H.

In some embodiments of compounds of formula II wherein n is 1 and X³ isCR¹²R¹³ (i.e., compounds of any of formulae III, IIIa, and IIIb) each ofR¹² and R¹³ is H or C₁₋₆ alkyl. In some embodiments, each of R¹² and R¹³is H.

In some embodiments of compounds of formula II, III or IV wherein

is a double bond and m is 0 (i.e., compounds of formulae IIIa or IVa),R¹ is H or C₁₋₆ alkyl. In some embodiments, R¹ is H.

In some embodiments of compounds of formula II, III or IV wherein

is a single bond and m is 1 (i.e., compounds of formulae IIIb or IVb),each of R¹ and R² is H or C₁₋₆ alkyl. In some embodiments, each of R¹and R² is H.

In some embodiments of compounds of formula II,

is a double bond; m is 0; X¹ is CR⁶R⁷, X² is NR⁸; n is 1; X³ is CR¹²R¹³;and each of R¹, R³, R⁴, R⁶, R⁷, R¹² and R¹³ is H. In other embodiments,

is a single bond; m is 1; X¹ is CR⁶R⁷, X² is NR⁸; n is 1; X³ is CR¹²R¹³;and each of R¹, R², R³, R⁴, R⁶, R⁷, R¹² and R¹³ is H.

In some embodiments, X¹ is NR⁵ and X² is CR⁹R¹⁰, i.e., compounds havingthe formula V:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein

Z¹, Z², R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰, X³, n and m are as defined aboveand herein. In certain preferred embodiments, Z¹ and Z² are both OH.

Embodiments of compounds of formula V include compounds of formula VI(i.e., wherein n is 1 and X³ is CR¹²R¹³):

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein

Z¹, Z², R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰, R¹², R¹³ and m are as defined aboveand herein. In certain preferred embodiments, Z¹ and Z² are both OH.

Formula VI also encompasses compounds of the formula VIa or VIb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein Z¹, Z², R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰, R¹² andR¹³ are as defined above and herein. In certain preferred embodiments,Z¹ and Z² are both OH.

Other embodiments of compounds of formula V include compounds of formulaVII (i.e., wherein n is 0):

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein

Z¹, Z², R¹, R², R³, R⁴, R⁵, R⁹, R¹⁰ and m are as defined above andherein. In certain preferred embodiments, Z¹ and Z² are both OH.

Formula VII also encompasses compounds of the formulae VIIa or VIIb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein Z¹, Z², R¹, R², R³, R⁴, R⁵, R⁹ and R¹⁹ are asdefined above and herein. In certain preferred embodiments, Z¹ and Z²are both OH.

In embodiments of compounds having any of formulae V, VI, VIa, VIb, VII,VIIa, and VIIb, R⁵ is not H. In certain embodiments, R⁵ is not —CH³. Incertain embodiments, R⁵ is selected from C₁₋₆ alkyl, —C(O)R²⁰,—C(O)OR²¹, —C(O)NR²²R²³, S(O)₂R²⁴, and —(CH₂)_(p)—R²⁵.

In some embodiments wherein R⁵ is —C(O)R²⁰, R²⁰ is selected from C₁₋₆alkyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10membered heteroaryl, and —(CH₂)_(q)—R²⁸.

In some embodiments, wherein R⁵ is —C(O)R²⁰, R²⁰ is —(CH₂)_(q)—R²⁸, andR²⁸ is selected from C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, and 5-10 membered heteroaryl. In some embodiments, q is 1or 2 and R²⁸ is C₆₋₁₀ aryl or 5-10 membered heteroaryl. In someembodiments, q is 3 or 4 and R²⁸ is C₆₋₁₀ aryl or 5-10 memberedheteroaryl. In some embodiments, R²⁸ is phenyl. In other embodiments,R²⁸ is 5-10 membered heteroaryl (e.g., pyridyl, indolyl, benzofuranyl orbenzothiophenyl).

In some embodiments, wherein R⁵ is —C(O)R²⁰, R²⁰ is —(CH₂)_(q)—R²⁸, andR²⁸ is —NR³²R³³. In some embodiments, R³² and R³³ each independently isselected from H, C₁₋₆ alkyl, and C₇₋₁₂ aralkyl. In certain embodiments,q is 1 or 2. In certain embodiments, q is 1. In some embodiments, one ofR³² and R³³ is H and the other is C₁₋₆ alkyl or C₇₋₁₂ aralkyl (e.g.,benzyl). In other embodiments each of R³² and R³³ independently is C₁₋₆alkyl or C₇₋₁₂ aralkyl (e.g., benzyl).

In some embodiments, R⁵ is —C(O)OR²¹ and R²¹ is selected from C₁₋₆ alkyland —(CH₂)_(q)—R²⁸. In certain embodiments, q is 1 or 2 and R²⁸ isselected from C₆₋₁₀ aryl and 5-10 membered heteroaryl. In someembodiments, R²¹ is benzyl.

In some embodiments, R⁵ is —C(O)NR²²R²³ and R²² and R²³ eachindependently is selected from H, C₁₋₆ alkyl, and —(CH₂)_(r)—R²⁹. Incertain embodiments, r is 1 or 2. In certain embodiments, r is 1. Insome embodiments, R²⁹ is C₆₋₁₀ aryl or 5-10 membered heteroaryl. In someembodiments, R²⁹ is phenyl. In some embodiments, one of R²² and R²³ is Hand the other is C₁₋₆ alkyl or —(CH₂)_(r)—R²⁹. In other embodiments,each of R²² and R²³ independently is C₁₋₆ alkyl or —(CH₂)_(r)—R²⁹. Insome embodiments, —(CH₂)_(r)—R²⁹ is benzyl (i.e., r is 1 and R²⁹ isphenyl).

In some embodiments, R⁵ is —S(O)₂R²⁴ and R²⁴ is selected from C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and —(CH₂)_(t)—R³⁹. Incertain embodiments, R²⁴ is phenyl.

In some embodiments, R⁵ is —(CH₂)_(p)—R²⁵ and R²⁵ is selected from C₆₋₁₀aryl and 5-10 membered heteroaryl. In some embodiments, p is 1 or 2, orp is 1. In certain embodiments, R²⁵ is phenyl. In other embodiments, R²⁵is 5-10 membered heteroaryl (e.g., pyridyl, indolyl, benzofuranyl orbenzothiophenyl).

In certain embodiments of compounds having any of formulae V, VI, VIa,VIb, VII, VIIa, and VIIb, each of R³ and R⁴ is H or C₁₋₆ alkyl. In someembodiments, each of R³ and R⁴ is H.

In certain embodiments of compounds having any of formulae V, VI, VIa,VIb, VII, VIIa, and VIIb, each of R⁹ and R¹⁰ is H or C₁₋₆ alkyl. In someembodiments, each of R⁹ and R¹⁰ is H.

In some embodiments of compounds of formula V wherein n is 1 and X³ isCR¹²R¹³ (i.e., compounds of any of formulae VI, VIa, and VIb) each ofR¹² and R¹³ is H or C₁₋₆ alkyl. In some embodiments, each of R¹² and R¹³is H.

In some embodiments of compounds of formula V, VI or VII wherein

is a double bond and m is 0 (i.e., compounds of formulae VIIa or VIIa),R¹ is H or C₁₋₆ alkyl. In some embodiments, R¹ is H.

In some embodiments of compounds of formula V, VI or VII, wherein

is a single bond and m is 1 (i.e., compounds of formulae VIIb or VIIb),each of R¹ and R² is H or C₁₋₆ alkyl. In some embodiments, each of R¹and R² is H.

In some embodiments of compounds of formula V,

is a double bond; m is 0; X¹ is NR⁸; X² is CR⁹R¹⁰; n is 1; X³ isCR¹²R¹³; and each of R¹, R³, R⁴, R⁹, R¹⁰, R¹² and R¹³ is H. In otherembodiments,

is a single bond; m is 1; X¹ is NR⁸; X² is CR⁹R¹⁰; n is 1; X³ isCR¹²R¹³; and each of R¹, R², R³, R⁴, R⁹, R¹⁰, R¹² and R¹³ is H.

In some embodiments, X¹ is CR⁶R⁷, X² is CR⁹R¹⁰, and X³ is NR¹¹, i.e.,compounds of the formula VIII:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein

Z¹, Z², R¹, R², R³, R⁴, R⁶, R⁷, R⁹, R¹⁰, R¹¹ and m are as defined aboveand herein. In certain preferred embodiments, Z¹ and Z² are both OH.Formula VIII also encompasses compounds of the formulae VIIIa or VIIIb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein Z¹, Z², R¹, R², R³, R⁴, R⁶, R⁷, R⁹, R¹⁰ and R¹¹are as defined above and herein. In certain preferred embodiments, Z¹and Z² are both OH.

In some embodiments of compounds having any of formulae VIII, VIIIa, andVIIIb, R¹¹ is not H. In certain embodiments, R¹¹ is not —CH³. R¹¹ isselected from C₁₋₆ alkyl, —C(O)R²⁰, —C(O)OR²¹, —C(O)NR²²R²³, S(O)₂ ²⁴,and —(CH₂)_(p)—R²⁵.

In some embodiments wherein R¹¹ is —C(O)R²⁰, R²⁰ can be selected fromC₁₋₆ alkyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl,5-10 membered heteroaryl, and —(CH₂)_(q)—R²⁸.

In some embodiments, wherein R¹¹ is —C(O)R²⁰, R²⁰ is —(CH₂)_(q)—R²⁸, andR²⁸ is selected from C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedheterocyclyl, and 5-10 membered heteroaryl. In some embodiments, q is 1or 2 and R²⁸ is C₆₋₁₀ aryl or 5-10 membered heteroaryl. In someembodiments, q is 3 or 4 and R²⁸ is C₆₋₁₀ aryl or 5-10 memberedheteroaryl. In some embodiments, R²⁸ is phenyl. In other embodiments,R²⁸ is 5-10 membered heteroaryl (e.g., pyridyl, indolyl, benzofuranyl orbenzothiophenyl).

In some embodiments, wherein R¹¹ is —C(O)R²⁰, R²⁰ is —(CH₂)_(q)—R²⁸, andR²⁸ is —NR³²R³³. In some embodiments, R³² and R³³ each independently isselected from H, C₁₋₆ alkyl, and C₇₋₁₂ aralkyl. In certain embodiments,q is 1 or 2, or q is 1. In some embodiments, one of R³² and R³³ is H andthe other is C₁₋₆ alkyl or C₇₋₁₂ aralkyl (e.g., benzyl). In otherembodiments each of R³² and R³³ independently is C₁₋₆ alkyl or C₇₋₁₂aralkyl (e.g., benzyl).

In some embodiments, R¹¹ is —C(O)OR²¹ and R²¹ is selected from C₁₋₆alkyl and —(CH₂)_(q)—R²⁸. In certain embodiments, q is 1 or 2 and R²⁸ isselected from C₆₋₁₀ aryl and 5-10 membered heteroaryl. In someembodiments, R²¹ is benzyl.

In some embodiments, R¹¹ is —C(O)NR²²R²³ and R²² and R²³ eachindependently is selected from H, C₁₋₆ alkyl, and —(CH₂)_(r)—R²⁹. Incertain embodiments, r is 1 or 2. In certain embodiments, r is 1. Insome embodiments, R²⁹ is C₆₋₁₀ aryl or 5-10 membered heteroaryl. In someembodiments, R²⁹ is phenyl. In some embodiments, one of R²² and R²³ is Hand the other is C₁₋₆ alkyl or —(CH₂)_(r)—R²⁹. In other embodiments,each of R²² and R²³ independently is C₁₋₆ alkyl or —(CH₂)_(r)—R²⁹. Insome embodiments, —(CH₂)_(r)—R²⁹ is benzyl (i.e., r is 1 and R²⁹ isphenyl).

In some embodiments, R¹¹ is —S(O)₂R²⁴ and R²⁴ is selected from C₁₋₆alkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, and —(CH₂)_(t)—R³⁰. Incertain embodiments, R²⁴ is phenyl.

In some embodiments, R¹¹ is —(CH₂)_(p)—R²⁵ and R²⁵ is selected fromC₆₋₁₀ aryl and 5-10 membered heteroaryl. In some embodiments, p is 1 or2. In certain embodiments, p is 1. In certain embodiments, R²⁵ isphenyl. In other embodiments, R²⁵ is 5-10 membered heteroaryl (e.g.,pyridyl, indolyl, benzofuranyl or benzothiophenyl).

In certain embodiments of compounds having any of formulae VIII, VIIIa,and VIIIb, each of R³ and R⁴ is H or C₁₋₆ alkyl. In some embodiments,each of R³ and R⁴ is H.

In certain embodiments of compounds having any of formulae VIII, VIIIa,and VIIIb, each of R⁶ and R⁷ is H or C₁₋₆ alkyl. In some embodiments,each of R⁶ and R⁷ is H.

In certain embodiments of compounds having any of formulae VIII, VIIIa,and VIIIb, each of R⁹ and R¹⁹ is H or C₁₋₆ alkyl. In some embodiments,each of R⁹ and R¹⁹ is H.

In embodiments of compounds of formula VIII wherein

is a double bond and m is 0 (i.e., compounds of formula VIIIa), R¹ is Hor C₁₋₆ alkyl. In some embodiments, R¹ is H.

In embodiments of compounds of formula VIII wherein

is a single bond and m is 1 (i.e., compounds of formula VIIIb), each ofR¹ and R² is H or C₁₋₆ alkyl. In some embodiments, each of R¹ and R² isH.

In some embodiments of compounds of formula VIII,

is a double bond; m is 0; X¹ is CR⁶R⁷; X² is CR⁹R¹⁰; n is 1; X³ is NR¹¹;and each of R¹, R³, R⁴, R⁶, R⁷, R⁹ and R¹⁰ is H. In other embodiments,

is a single bond; m is 1; X¹ is CR⁶R⁷; X² is CR⁹R¹⁰; n is 1; X³ is NR¹¹;and each of R¹, R², R³, R⁴, R⁶, R⁷, R⁹ and R¹⁰ is H.

In some embodiments of compounds of formulae I, II, III, IIIa, IIIb, IV,IVa, IVb, V, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, Z¹ is—OR¹⁴ and Z² is —OR¹⁵. In certain embodiments R¹⁴ is H and R¹⁵ is H.

In other embodiments, Z¹ and Z² taken together with the boron atom towhich they are bound, form a 5- to 8-membered ring having at least oneO, S, N or NR^(A) atom directly attached to the boron atom, whereinR^(A) is selected from hydrogen, —SO₂R^(B), —SOR^(B), —C(O)R^(B),—CO₂R^(B), —C(O)N(R^(B))₂, C₁₋₈ alkyl, C₂₋₆ alkenyl, C₂₋₈ alkynyl, C₃₋₁₀carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl; and each instance of R^(B) is, independently, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, or 5-10 membered heteroaryl. In someembodiments, the 5- to 8-membered ring is with one or more groupsselected from halogen, oxo (═O), —SO₂R^(C), —SOR^(C), —C(O)R^(C),—C(O)OR^(C), —C(O)N(R^(C))₂, —C(O)NHR^(C), C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl,or 5-10 membered heteroaryl groups, or two groups present on the ringare joined to form a 5- to 8-membered monocylic or bicyclic ringoptionally containing one or more heteroatoms selected from O, S, N orNR^(A); wherein each instance of R^(C) is independently, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, or 5-10 membered heteroaryl.

For example, in certain embodiments, Z¹ and Z², taken together with theboron atom to which they are bound, form an optionally substituted5-membered ring having at least one O, S or NR^(A) atom directlyattached to the boron atom. Exemplary 5-membered rings include, but arenot limited to:

wherein R^(A) is as defined herein.

In other embodiments, Z¹ and Z², taken together with the boron atom towhich they are bound, form a 6-membered ring having at least one O, S orNR^(A) atom directly attached to the boron atom. Exemplary 6-memberedrings include, but are not limited to:

In yet other embodiments, Z¹ and Z² form an 8-membered ring having atleast one O, S or NR^(A) atom directly attached to the boron atom.Exemplary 8-membered ring structures include, but are not limited to:

wherein R^(A) is as defined herein.

In certain embodiments, a compound of formula I or a subset thereof(e.g., a compound of formulae II, III, IIIa, IIIb, V, VI, VIa, VIb,VIII, VIIIa, or VIIIb) is not any one of the following compounds:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

In certain embodiments, a compound of formula I or a subset thereof(e.g., a compound of formulae IV, IVa, IVb, VII, VIIa or VIIb) is notany one of the following compounds:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

DEFINITIONS

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed inside cover, and specificfunctional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Certain compounds of the present invention can comprise one or moreasymmetric centers, and thus can exist in various isomeric forms, e.g.,enantiomers and/or diastereomers. The compounds provided herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer. Incertain embodiments, the compounds of the invention are enantiopurecompounds. In certain other embodiments, mixtures of stereoisomers areprovided.

Furthermore, certain compounds, as described herein can have one or moredouble bonds that can exist as either the cis or trans, or the E or Zisomer, unless otherwise indicated. The invention additionallyencompasses the compounds as individual isomers substantially free ofother isomers, and alternatively, as mixtures of various isomers, e.g.,racemic mixtures of E/Z isomers or mixtures enriched in one E/Z isomer.

Where a particular enantiomer is preferred, it can be providedsubstantially free of the corresponding enantiomer, i.e., opticallyenriched. “Optically-enriched,” as used herein, means that the compoundis made up of a greater proportion of one enantiomer compared to theother. In certain embodiments the compound is made up of at least about90% by weight of a preferred enantiomer. In other embodiments thecompound is made up of at least about 95%, 98%, or 99% by weight of apreferred enantiomer. Preferred enantiomers can be isolated frommixtures by methods known to those skilled in the art, including chiralhigh pressure liquid chromatography (HPLC) and the formation andcrystallization of chiral salts; or preferred enantiomers can beprepared by asymmetric syntheses. See, for example, Jacques, et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen,S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein a “direct bond” or “covalent bond” refers to a singlebond.

As used herein, the term “boronic acid” refers to any chemical compoundcomprising a —B(OH)₂ moiety. Arylboronic acid compounds readily formoligomeric anhydrides by dehydration of the boronic acid moiety (see,for example, Snyder et al., J. Am. Chem. Soc. (1958) 80: 3611). Thus,unless otherwise apparent from context, the term “boronic acid” isexpressly intended to encompass free boronic acids, oligomericanhydrides, including, but not limited to, dimers, trimers, andtetramers, and mixtures thereof.

The terms “boronic ester”, “borinic acid” and “borinic ester” are artunderstood terms referring to a —B(OR)₂ moiety, a —B(R)OH moiety and a—B(R)OR moiety, respectively, wherein R is a group other than hydrogen(e.g., an C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, carbocycyl,heterocycyl, aryl, or heteroaryl group; or two R groups are joined toform a 5- to 8-membered ring optionally containing 1 to 4 heteroatoms).

As used herein, alone or as part of another group, “halo” and “halogen”refer to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), or iodine (iodo, —I).

As used herein, alone or as part of another group, “alkyl” refers to amonoradical of a straight-chain or branched saturated hydrocarbon grouphaving from 1 to 8 carbon atoms (“C₁₋₈ alkyl”). In some embodiments, analkyl group can have from 1 to 6 carbon atoms (“C₁₋₆ alkyl”). In someembodiments, an alkyl group can have from 1 to 4 carbon atoms (“C₁₋₄alkyl”). Examples of C₁₋₄ alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert butyl. Examples of C₁₋₆alkyl groups include the aforementioned C₁₋₄ alkyl groups as well aspentyl, isopentyl, neopentyl, hexyl and the like. Additional examples ofalkyl groups include heptyl, octyl and the like. Unless otherwisespecified, each instance of an alkyl group is independentlyunsubstituted or substituted with 1-5 groups as described below.

As used herein, alone or as part of another group, “alkenyl” refers to amonoradical of a straight-chain or branched hydrocarbon group havingfrom 2 to 8 carbon atoms and one or more carbon-carbon double bonds(“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group can have from 2to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenylgroup can have from 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). The one ormore carbon-carbon double bonds can be internal (such as in 2-butenyl)or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenyl groupsinclude ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,butadienyl and the like. Examples of C₂₋₆ alkenyl groups include theaforementioned C₂₋₄ alkenyl groups as well as pentenyl, pentadienyl,hexenyl and the like. Additional examples of alkenyl include heptenyl,octenyl, octatrienyl and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently unsubstituted orsubstituted with 1-5 groups as described below.

As used herein, alone or as part of another group, “alkynyl” refers to amonoradical of a straight-chain or branched hydrocarbon group havingfrom 2 to 8 carbon atoms and one or more carbon-carbon triple bonds(“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group can have from 2to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, an alkynylgroup can have from 2 to 4 carbon atoms (“C₂₋₄ alkynyl”). The one ormore carbon-carbon triple bonds can be internal (such as in 2-butynyl)or terminal (such as in 1-butynyl). Examples of C₂₋₄ alkynyl groupsinclude ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and thelike. Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄alkynyl groups as well as pentynyl, hexynyl and the like. Additionalexamples of alkynyl include heptynyl, octynyl and the like. Unlessotherwise specified, each instance of an alkynyl group is independentlyunsubstituted or substituted with 1-5 groups as described below.

As used herein, alone or as part of another group, “alkylene” refers toa diradical of a straight-chain or branched saturated alkyl group havingfrom 1 to 6 carbon atoms (“C₁₋₆ alkylene”). In some embodiments, analkylene group can have from 1 to 4 carbon atoms (“C₁₋₄ alkylene”). Insome embodiments, an alkylene group can have from 1 to 2 carbon atoms(“C₁₋₂ alkylene”). Examples of C₁₋₂ alkylene groups include methyleneand ethylene. Examples of C₁₋₄ alkylene groups include theaforementioned C₁₋₂ alkylene groups as well as trimethylene(1,3-propanediyl), propylene (1,2-propanediyl), tetramethylene(1,4-butanediyl), butylene (1,2-butanediyl), 1,3-butanediyl,2-methyl-1,3-propanediyl and the like. Examples of C₁₋₆ alkylene groupsinclude the aforementioned C₁₋₄ alkylene groups as well aspentamethylene (1,5-pentanediyl), pentylene (1,2-pentanediyl),hexamethylene (1,6-hexanediyl), hexylene (1,2-hexanediyl),2,3-dimethyl-1,4-butanediyl and the like. In some embodiments, analkylene group is an α,ω-diradical. Examples of α,ω-diradical alkylenegroups include methylene, ethylene, trimethylene, tetramethylene,pentamethylene and hexamethylene. Unless otherwise specified, eachinstance of an alkylene group is independently unsubstituted orsubstituted with 1-5 groups as described below.

As used herein, alone or as part of another group, “alkenylene” refersto a diradical of a straight-chain or branched alkenyl having from 2 to6 carbon atoms and one or more carbon-carbon double bonds (“C₂₋₆alkenylene”). In some embodiments, an alkenylene group can have from 2to 4 carbon atoms (“C₂₋₄ alkenylene”). In some embodiments, analkenylene group can have 2 carbon atoms, i.e., ethenediyl. The one ormore carbon-carbon double bonds can be internal (such as in1,4-but-2-enediyl) or terminal (such as in 1,4-but-1-enediyl). Examplesof C₂₋₄ alkenylene groups include ethenediyl, 1,2-propenediyl,1,3-propenediyl, 1,4-but-1-enediyl, 1,4-but-2-enediyl and the like.Examples of C₂₋₆ alkenylene groups include the aforementioned C₂₋₄alkenylene groups as well as 1,5-pent-1-enediyl, 1,4-pent-2-enediyl,1,6-hex-2-enediyl, 2,5-hex-3-enediyl, 2-methyl-1,4-pent-2-enediyl andthe like. In some embodiments, an alkenylene group is an α,ω-diradical.Examples of α,ω-diradical alkenylene groups include ethenediyl,1,3-propenediyl, 1,4-but-2-enediyl, 1,5-pent-1-enediyl,1,6-hex-3-enediyl and the like. Unless otherwise specified, eachinstance of an alkenylene group is independently unsubstituted orsubstituted with 1-5 groups as described below.

As used herein, alone or as part of another group, “alkynylene” refersto a diradical of a straight-chain or branched alkynyl group having from2 to 6 carbon atoms and one or more carbon-carbon triple bonds (“C₂₋₆alkynylene”). In some embodiments, an alkynylene group can have from 2to 4 carbon atoms (“C₂₋₄ alkynylene”). In some embodiments, analkynylene group can have 2 carbon atoms, i.e., ethynediyl. The one ormore carbon-carbon triple bonds can be internal (such as in1,4-but-2-ynediyl) or terminal (such as in 1,4-but-1-ynediyl). Examplesof C₂₋₄ alkynylene groups include ethynediyl, propynediyl,1,4-but-1-ynediyl, 1,4-but-2-ynediyl and the like. Examples of C₂₋₆alkynylene groups include the aforementioned C₂₋₄ alkynylene groups aswell as 1,5-pent-1-ynediyl, 1,4-pent-2-ynediyl, 1,6-hex-2-ynediyl,2,5-hex-3-ynediyl, 3-methyl-1,5-hex-1-ynediyl and the like. In someembodiments, an alkynylene group is an α,ω-diradical. Examples ofα,ω-diradical alkynylene groups include ethynediyl, propynediyl,1,4-but-2-ynediyl, 1,5-pent-1-ynediyl, 1,6-hex-3-ynediyl and the like.Unless otherwise specified, each instance of an alkynylene group isindependently unsubstituted or substituted with 1-5 groups as describedbelow.

As used herein, alone or as part of another group, “perhaloalkyl” refersto an alkyl group having from 1 to 6 carbon atoms, wherein all of thehydrogen atoms are each independently replaced with fluoro or chloro. Insome embodiments, all of the hydrogen atoms are each replaced withfluoro. In some embodiments, all of the hydrogen atoms are each replacedwith chloro. Examples of perhaloalkyl groups include —CF₃, —CF₂CF₃,—CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl and the like.

As used herein, alone or as part of another group, “alkoxy” or“alkyloxy” refers to a —O-alkyl group having from 1 to 8 carbon atoms(“C₁₋₈ alkoxy”). In some embodiments, an alkoxy group can have from 1 to6 carbon atoms (“C₁₋₆ alkoxy”). In some embodiments, an alkoxy group canhave from 1 to 4 carbon atoms (“C₁₋₄ alkoxy”). Examples of C₁₋₄ alkoxygroups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxyand the like. Examples of C₁₋₆ alkoxy groups include the aforementionedC₁₋₄ alkoxy groups as well as pentyloxy, isopentyloxy, neopentyloxy,hexyloxy and the like. Additional examples of alkoxy groups includeheptyloxy, octyloxy and the like. Unless otherwise specified, eachinstance of an alkoxy group is independently unsubstituted orsubstituted with 1-5 groups as described below.

As used herein, alone or as part of another group, “perhaloalkoxy”refers to an alkoxy group having from 1 to 3 carbon atoms, wherein allof the hydrogen atoms are each independently replaced with fluoro orchloro. In some embodiments, all of the hydrogen atoms are each replacedwith fluoro. In some embodiments, all of the hydrogen atoms are eachreplaced with chloro. Examples of perhaloalkoxy groups include —OCF₃,—OCF₂CF₃, —OCF₂CF₂CF₃, —OCCl₃, —OCFCl₂, —OCF₂Cl and the like.

As used herein, alone or as part of another group, “alkylthio” refers toan —S-alkyl group having from 1 to 8 carbon atoms. In some embodiments,an alkylthio group can have from 1 to 6 carbon atoms. In someembodiments, an alkylthio group can have from 1 to 4 carbon atoms.Examples of C₁₋₄ alkylthio groups include methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio and the like.Examples of C₁₋₆ alkylthio groups include the aforementioned C₁₋₄alkylthio groups as well as pentylthio, isopentylthio, hexylthio and thelike. Additional examples of alkylthio groups include heptylthio,octylthio and the like. Unless otherwise specified, each instance of analkylthio group is independently unsubstituted or substituted with 1-5groups as described below.

As used herein, alone or as part of another group, “carbocyclyl” or“carbocycle” refers to a radical of a non-aromatic cyclic hydrocarbongroup having from 3 to 10 ring carbon atoms (“C₃₋₁₀ carbocyclyl”). Insome embodiments, a carbocyclyl group can have from 3 to 8 ring carbonatoms (“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group canhave from 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Examples ofC₃₋₆ carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like.Examples of C₃₋₈ carbocyclyl groups include the aforementioned C₃₋₆carbocyclyl groups as well as cycloheptyl, cycloheptadienyl,cycloheptatrienyl, cyclooctyl, bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl and the like. Examples of C₃₋₁₀ carbocyclyl groupsinclude the aforementioned C₃₋₈ carbocyclyl groups as well asoctahydro-1H-indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and thelike. As the foregoing examples illustrate, in some embodiments acarbocyclyl group can be monocyclic (“monocyclic carbocyclyl”) orbicyclic (“bicyclic carbocyclyl”, e.g., containing a fused, bridged orspiro ring system), and can be saturated or can contain one or morecarbon-carbon double or triple bonds. “Carbocyclyl” also refers to aphenyl group (as defined below) fused to a monocyclic carbocyclyl group.Examples of such carbocyclyl groups include1,2,3,4-tetrahydronaphthalene (e.g., 1,2,3,4-tetrahydronaphthalen-1-yl,1,2,3,4-tetrahydronaphthalen-5-yl, and the like), 2,3-dihydro-1H-indene(e.g., 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-4-yl, and thelike), indene (e.g., 1H-inden-1-yl, 1H-inden-7-yl, and the like),5,6,7,8-tetrahydroquinoline (e.g., 5,6,7,8-tetrahydroquinolin-5-yl,5,6,7,8-tetrahydroquinolin-2-yl, and the like),4,5,6,7-tetrahydro-1H-indole (e.g., 4,5,6,7-tetrahydro-1H-indol-4-yl,4,5,6,7-tetrahydro-1H-indol-3-yl, and the like),4,5,6,7-tetrahydrobenzofuran (e.g., 4,5,6,7-tetrahydrobenzofuran-7-yl,4,5,6,7-tetrahydrobenzofuran-2-yl, and the like) and the like. Unlessotherwise specified, each instance of a carbocyclyl or carbocycle groupis independently unsubstituted or substituted with 1-5 groups asdescribed below.

In some embodiments, “carbocyclyl” or “carbocycle” can refer to amonocyclic, saturated carbocyclyl group (“cycloalkyl”) having from 3 to10 ring carbon atoms (“C₃₋₁₀ cycloalkyl”). In some embodiments, acycloalkyl group can have from 3 to 6 ring carbon atoms (“C₃₋₆cycloalkyl”). In some embodiments, a cycloalkyl group can have from 5 to6 ring carbon atoms (“C₅₋₆ cycloalkyl”). Examples of C₅₋₆ cycloalkylgroups include cyclopentyl and cyclohexyl. Examples of C₃₋₆ cycloalkylgroups include the aforementioned C₅₋₆ cycloalkyl groups as well ascyclopropyl and cyclobutyl. Examples of C₃₋₈ cycloalkyl groups includethe aforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl andcyclooctyl. Unless otherwise specified, each instance of a cycloalkylgroup is independently unsubstituted or substituted with 1-5 groups asdescribed below.

As used herein, alone or as part of another group, “heterocyclyl” or“heterocycle” refers to a radical of a 3- to 10-membered non-aromaticring system having ring carbon atoms and 1 to 4 ring heteroatoms, eachheteroatom independently selected from nitrogen, oxygen and sulfur. Insome embodiments, a heterocyclyl group can have from 3 to 7 ring atomsselected from carbon atoms and 1 to 3 heteroatoms, each heteroatomindependently selected from nitrogen, oxygen and sulfur. In someembodiments, a heterocyclyl group can have from 5 to 7 ring atomsselected from carbon atoms and 1 or 2 heteroatoms, each heteroatomindependently selected from nitrogen, oxygen and sulfur. In someembodiments, a heterocyclyl group can have from 5 to 6 ring atomsselected from carbon atoms and 1 to 3 heteroatoms, each heteroatomindependently selected from nitrogen, oxygen and sulfur. Heterocyclylgroups can be saturated or can contain one or more carbon-carbon doublebonds, carbon-nitrogen double bonds, or carbon-carbon triple bonds. Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits.

Examples of heterocyclyl groups with 1-2 ring heteroatoms includeoxiranyl, aziridinyl, oxetanyl, azetidinyl, pyrrolidinyl,dihydropyrrolyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl,tetrahydropyridinyl, dihydropyridinyl, piperazinyl, tetrahydropyranyl,dioxanyl, morpholinyl, azepanyl, diazepanyl, diazepinyl, oxepanyl,dioxepanyl, oxazepanyl, oxazepinyl and the like. Examples ofheterocyclyl groups with 1-3 heteroatoms include the aforementionedheterocyclyl groups as well as triazolidinyl, oxadiazolidinyl,triazinanyl and the like. Heterocyclyl groups can be monocyclic(“monocyclic heterocyclyl”) as in the aforementioned examples, bicyclic(“bicyclic heterocyclyl”), or tricyclic (“tricyclic heterocyclyl”).Bicyclic heterocyclyl groups can include one or more heteroatoms in oneor both rings. Examples of such bicyclic heterocyclyl groups includetetrahydroindolyl, decahydroquinolinyl, decahydroisoquinolinyl,octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole and thelike.

“Heterocyclyl” or “heterocycle” also refers to a radical of a 5- to10-membered fused ring system having ring carbon atoms and 1 to 4 ringheteroatoms, each heteroatom independently selected from nitrogen,oxygen and sulfur, wherein one ring is aromatic and the other isnon-aromatic. In some embodiments, at least one heteroatom is present ineither the aromatic or non-aromatic ring, while in other embodiments, atleast one heteroatom is present in both rings. In heterocyclyl groupsthat contain one or more nitrogen atoms, the point of attachment can bea carbon or nitrogen atom, as valency permits. Examples of suchheterocyclyl groups include indolinyl (e.g., indolin-1-yl, indolin-4-yl,and the like), isoindolinyl (e.g., isoindolin-1-yl, isoindolin-4-yl, andthe like), 4,5,6,7-tetrahydro-1H-indolyl (e.g.,tetrahydro-1H-indol-2-yl, 4,5,6,7-tetrahydro-1H-indol-4-yl, and thelike), dihydrobenzofuranyl (e.g., dihydrobenzofuran-3-yl,dihydrobenzofuran-5-yl, and the like), 4,5,6,7-tetrahydrobenzofuranyl(e.g., 4,5,6,7-tetrahydrobenzofuran-2-yl,4,5,6,7-tetrahydrobenzofuran-5-yl, and the like), dihydrobenzothienyl(e.g., dihydrobenzothien-2-yl, dihydrobenzothien-4-yl, and the like),4,5,6,7-tetrahydrobenzothiophenyl (e.g.,4,5,6,7-tetrahydrobenzothiophen-2-yl,4,5,6,7-tetrahydrobenzothiophen-7-yl, and the like),1,2,3,4-tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydroquinolin-1-yl,1,2,3,4-tetrahydroquinolin-7-yl, and the like), chromanyl (e.g.,chroman-2-yl, chroman-5-yl, and the like), chromenyl (chromen-4-yl,chromen-8-yl, and the like), thiochromanyl (e.g., thiochroman-3-yl,isochroman-7-yl, and the like), 1H-benzo[e][1,4]diazepinyl (e.g.,1H-benzo[e][1,4]diazepin-2-yl, 1H-benzo[e][1,4]diazepin-6-yl, and thelike), 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl (e.g.,2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl, and the like),4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl (e.g.,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridin-2-yl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridin-4-yl, and the like),1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl (e.g.,1,4,5,7-tetrahydropyrano[3,4-b]pyrrol-2-yl,1,4,5,7-tetrahydropyrano[3,4-b]pyrrol-4-yl, and the like),2,3-dihydrofuro[2,3-b]pyridinyl (e.g.,2,3-dihydrofuro[2,3-b]pyridin-3-yl, 2,3-dihydrofuro[2,3-b]pyridin-5-yl,and the like), 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl (e.g.,4,5,6,7-tetrahydrofuro[3,2-c]pyridin-2-yl,4,5,6,7-tetrahydrofuro[3,2-c]pyridin-5-yl, and the like),4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl (e.g.,4,5,6,7-tetrahydrothieno[3,2-b]pyridin-2-yl,4,5,6,7-tetrahydrothieno[3,2-b]pyridin-7-yl, and the like),5,6-dihydro-4H-furo[3,2-b]pyrrolyl (e.g.,5,6-dihydro-4H-furo[3,2-b]pyrrol-6-yl,5,6-dihydro-4H-furo[3,2-b]pyrrol-2-yl, and the like),6,7-dihydro-5H-furo[3,2-b]pyranyl (e.g.,6,7-dihydro-5H-furo[3,2-b]pyran-2-yl,6,7-dihydro-5H-furo[3,2-b]pyran-6-yl, and the like),5,7-dihydro-4H-thieno[2,3-c]pyranyl (e.g.,5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl,5,7-dihydro-4H-thieno[2,3-c]pyran-4-yl, and the like),1,2,3,4-tetrahydro-1,6-naphthyridinyl (e.g.,1,2,3,4-tetrahydro-1,6-naphthyridin-3-yl,1,2,3,4-tetrahydro-1,6-naphthyridin-8-yl, and the like), and the like.

Unless otherwise specified, each instance of a heterocyclyl group isindependently unsubstituted or substituted with 1-5 groups as describedbelow.

As used herein, alone or as part of another group, “aryl” refers to aradical of an aromatic monocyclic or bicyclic ring system having 6 or 10ring carbon atoms. Examples of such aryl groups include phenyl,1-naphthyl and 2-naphthyl. Unless otherwise specified, each instance ofan aryl group is independently unsubstituted or substituted with 1-5groups as described below.

The term “aralkyl” refers to an alkyl group substituted by an arylgroup, wherein the alkyl and aryl portions independently are asdescribed below.

As used herein, alone or as part of another group, “heteroaryl” refersto a radical of a 5- to 10-membered aromatic ring system having ringcarbon atoms and 1 to 4 ring heteroatoms, each heteroatom independentlyselected from nitrogen, oxygen and sulfur. Examples of such heteroarylgroups include pyrrolyl, furanyl (furyl), thiophenyl (thienyl),pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (pyridyl), pyridazinyl,pyrimdinyl, pyrazinyl, triazinyl, indolyl, benzofuranyl, benzothiophenyl(benzothienyl), indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl and the like. As theforegoing examples illustrate, in some embodiments a heteroaryl groupcan be monocyclic (“monocyclic heteroaryl”), and in some embodiments aheteroaryl group can be bicyclic (“bicyclic heteroaryl”). For bicyclicheteroaryl groups wherein one ring does not contain a heteroatom (e.g.,indolyl, quinolinyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl). Unless otherwise specified, each instance of a heteroarylgroup is independently unsubstituted or substituted with 1-5 groups asdescribed below.

The term “heteroaralkyl” refers to an alkyl group substituted by aheteroaryl group, wherein the alkyl and heteroaryl portionsindependently are as described below.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, alkyl, alkenyl, alkynyl, alkylene, alkenylene,alkynylene, alkoxy, alkylthio, carbocycle, heterocycle, aryl, aralkyl,heteroaryl, and heteroaralkyl groups as described above and herein aresubstituted or unsubstituted (i.e., optionally substituted). In general,the term “substituted”, whether preceded by the term “optionally” ornot, means that one or more hydrogens of the designated moiety arereplaced with a suitable substituent. Unless otherwise indicated, asubstituted group can have a suitable substituent at each substitutableposition of the group, and when more than one position in any givenstructure is substituted with more than one substituent, then thesubstituent can be either the same or different at these positions.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable compounds. The term“stable”, as used herein, refers to compounds that are not substantiallyaltered when subjected to conditions to allow for their production,detection, and, in certain embodiments, their recovery, purification,and/or use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a carbon atom are independentlyhalogen; —(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄—CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which can besubstituted with one or more R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which can besubstituted with R^(o); —CH═CHPh, which can be substituted with one ormore R^(o); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂;—(CH₂)₀₋₄N(R^(o))C(O)R^(o); —N(R^(o))C(S)R^(o);—(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o) ₂;—(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); (CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR^(o), —SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o);—(CH₂)₀₋₄C(O)NR^(o) ₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —SC(S)SR^(o),—(CH₂)₀₋₄OC(O)NR^(o) ₂; —C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o);—(CH₂)₀₋₄S(O)₂R^(o); —(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o);—S(O)₂NR^(o) ₂; —(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂;—N(R^(o))S(O)₂R^(o); —N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o);—P(O)R^(o) ₂; —OP(O)R^(o) ₂; —OP(O)(OR^(o))₂; SiR^(o) ₃; —(C₁₋₄alkylene)O—N(R^(o))₂; or —(C₁₋₄ alkylene)C(O)O—N(R^(o))₂, wherein eachR^(o) can be substituted as defined below and is independently hydrogen,C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ heteroalkyl, C₂₋₈heteroalkenyl, C₂₋₈ heteroalkynyl, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5- or6-membered saturated, partially unsaturated, or aromatic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with the atom(s) to which they are bound, form a3- to 12-membered saturated, partially unsaturated, or aromatic mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which can be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by twoindependent occurrences of R^(o) together with the atoms to which theyare bound), are independently halogen, —(CH₂)₀₋₂R^(●), —(CH₂)₀₋₂OH,—(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂, —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●),—(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH,—(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃,—OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄ alkylene)C(O)OR^(●), or —SSR^(●)wherein each R^(●) is unsubstituted or substituted with one or morehalogens, and is independently selected from C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5- or 6-membered saturated,partially unsaturated, or aromatic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(o) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom include thefollowing: ═O, ═S, ═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*,═NOR*, —O(C(R*₂))₂₋₃O—, or —S(C(R^(*) ₂))₂₋₃S—, wherein each independentoccurrence of R* is selected from hydrogen; C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, each of which can be substituted as defined below; or anunsubstituted 5- or 6-membered saturated, partially unsaturated, oraromatic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Suitable divalent substituents that arebound to vicinal substitutable carbons include: —O(CR*₂)₂₋₃O—, whereineach independent occurrence of R* is selected from hydrogen; C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, each of which can be substituted as definedbelow; or an unsubstituted 5- or 6-membered saturated, partiallyunsaturated, or aromatic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

Suitable substituents on a C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl R*group include halogen, —R^(●), —(haloR^(●)), —OH, —OR^(●), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or substituted with one or more halogens, and isindependently C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5- or 6-membered saturated, partially unsaturated, oraromatic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen include —R^(†),—NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†), —C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†),—S(O)₂R^(†), —S(O)₂NR^(†) ₂, —C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or—N(R^(†))S(O)₂R^(†); wherein each R^(†) is independently hydrogen; C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, each of which can be substituted asdefined below; unsubstituted —OPh; or an unsubstituted 5- or 6-memberedsaturated, partially unsaturated, or aromatic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with the atom(s) to which they are bound form anunsubstituted 3- to 12-membered saturated, partially unsaturated, oraromatic mono- or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

Suitable substituents on a C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynylR_(†) group are independently halogen, —R^(●), —OH, —OR^(●), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or substituted with one or more halogens, and isindependently C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5- or 6-membered saturated, partially unsaturated, oraromatic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In certain embodiments, each C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂ aralkyl, 3-10 memberedheterocyclyl, and 5-10 membered heteroaryl, alone or as part of anothergroup, is independently and with 1-5 substituents selected from halogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ perhaloalkyl, —OH, C₁₋₆alkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)₂, and —CN.

As used herein, “solvate” refers to a compound of the present inventionor a pharmaceutically acceptable salt or prodrug thereof, that furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

As used herein, and unless otherwise specified, the term “prodrug” meansa biologically active derivative of a compound that can hydrolyze,oxidize, or otherwise react under physiological conditions (in vitro orin vivo) to provide the pharmacologically active compound. Additionally,prodrugs can be converted to the compounds of the invention by chemicalor biochemical methods in an ex vivo environment. For example, prodrugscan be slowly converted to the compounds of the invention when placed ina transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent drug is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. Examples of prodrugs include, but are not limitedto, compounds that comprise biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Other examples of prodrugs includecompounds that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties. Thecompounds of the invention readily undergo dehydration to formoligomeric anhydrides by dehydration of the boronic acid moiety to formdimers, trimers, and tetramers, and mixtures thereof. These oligomericspecies hydrolyze under physiological conditions to reform the boronicacid. As such, the oligomeric anhydrides are contemplated as a “prodrug”of the compounds described herein, and can be used in the treatment ofdisorder and/or conditions a wherein the inhibition of FAAH provides atherapeutic effect.

Exemplary prodrugs of the compounds described herein include, but arenot limited to, compounds wherein Z¹ and Z² taken together form a 5- to8-membered ring having at least one heteroatom atom selected fromnitrogen, oxygen and sulfur directly attached to boron, wherein the ringis comprised of carbon atoms and optionally one or more additionalheteroatoms independently selected from nitrogen, oxygen and sulfur.

Other examples of prodrugs of the compounds described herein aretrifluoroborate prodrugs which hydrolyze to the boronic acid (i.e., —BF₃hydrolyzing to —B(OH)₂) at acidic pH. Salt forms of the boronic acid(e.g., Na⁺, Li⁺, Mg²⁺, Ca²⁺, and the like) are also considered prodrugsAmino acids can be used to form prodrugs, such as, for example, serineand cysteine protected boronic acids. 1,2 and 1,3 hydroxy sugars can beused to form prodrugs, such as, for example, glycerol, erythritol,threitol, ribitol, arabinitol, xylitol, allitol, altritol, galactitol,sorbitol, mannitol, and iditol protected boronic acids. Other sugarswhich are useful in the formation of prodrugs include, but are notlimited to, maltitol, lactitol, and isomalt; other monosaccharides whichinclude hexoses (e.g., allose, altrose, glucose, mannose, gulose, idose,galactose, talose) and pentoses (e.g., ribose, arabinaose, xylose,lyxose); pentaerythritols and structural derivatives thereof, such asmethylated, ethylated, acetate, ethoxylate, and propoxylate derivatives;and phenolic polyols such as 1,2,4 benzenetriol, 5-methylbenzene-1,2,3-triol, 2,3,4-trihydroxybenzaldehyde, and3,4,5-trihydroxybenzamide. Prodrugs also include NMIDA-derivatives.

Pharmaceutically Acceptable Compositions and Formulations

In certain embodiments, the present invention provides apharmaceutically acceptable composition comprising a compound of any offormulae I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa, and VIIIb, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, or mixture thereof, and apharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients include any and all solvents,diluents or other liquid vehicles, dispersion or suspension aids,surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. General considerations in theformulation and/or manufacture of pharmaceutically acceptablecompositions agents can be found, for example, in Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980), and Remington: The Science andPractice of Pharmacy, 21^(st) Edition (Lippincott Williams & Wilkins,2005).

Pharmaceutically acceptable compositions described herein can beprepared by any method known in the art of pharmacology. In general,such preparatory methods include the steps of bringing the activeingredient into association with an excipient and/or one or more otheraccessory ingredients, and then, if necessary and/or desirable, shapingand/or packaging the product into a desired single- or multi-dose unit.

Pharmaceutically acceptable compositions can be prepared, packaged,and/or sold in bulk, as a single unit dose, and/or as a plurality ofsingle unit doses. As used herein, a “unit dose” is discrete amount ofthe pharmaceutically acceptable composition comprising a predeterminedamount of the active ingredient. The amount of the active ingredient isgenerally equal to the dosage of the active ingredient which would beadministered to a subject and/or a convenient fraction of such a dosagesuch as, for example, one-half or one-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutically acceptable composition of the invention will vary,depending upon the identity, size, and/or condition of the subjecttreated and further depending upon the route by which the composition isto be administered. By way of example, the composition can comprisebetween about 0.1% and about 100% (w/w) active ingredient, or betweenabout 2% and about 90% (w/w) active ingredient, or between about 5% andabout 80% (w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutically acceptable compositions include inertdiluents, dispersing and/or granulating agents, surface active agentsand/or emulsifiers, disintegrating agents, binding agents,preservatives, buffering agents, lubricating agents, and/or oils.Excipients such as cocoa butter and suppository waxes, coloring agents,coating agents, sweetening, flavoring, and perfuming agents can also bepresent in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, etc., and combinationsthereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, etc., and combinations thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g. acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]),long chain amino acid derivatives, high molecular weight alcohols (e.g.stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate,ethylene glycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acidesters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20],polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate[Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate[Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitanmonooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylenemonostearate [Myrj 45], polyoxyethylene hydrogenated castor oil,polyethoxylated castor oil, polyoxymethylene stearate, and Solutol),sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g.Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether[Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate,triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate,oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68,Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride,benzalkonium chloride, docusate sodium, etc. and/or combinationsthereof.

Exemplary binding agents include starch (e.g. cornstarch and starchpaste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghattigum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, microcrystalline cellulose, celluloseacetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum),and larch arabogalactan), alginates, polyethylene oxide, polyethyleneglycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes,water, alcohol, etc., and/or combinations thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, etc., and combinations thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, etc., and combinations thereof.

Exemplary oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary oils include, but are not limited to, butylstearate, caprylic triglyceride, capric triglyceride, cyclomethicone,diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil,octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms can comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and combinations thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, can depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form can comprise buffering agents.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They can optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. Solid compositions of asimilar type can be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active ingredients can be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms cancomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms can comprise bufferingagents. They can optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner Examples of embedding compositions which can be usedinclude polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compoundof this invention can include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier and/or any needed preservativesand/or buffers as may be required. Additionally, the present inventioncontemplates the use of transdermal patches, which often have the addedadvantage of providing controlled delivery of an active ingredient tothe body. Such dosage forms can be prepared, for example, by dissolvingand/or dispensing the active ingredient in the proper medium.Alternatively or additionally, the rate can be controlled by eitherproviding a rate controlling membrane and/or by dispersing the activeingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticallyacceptable compositions described herein include short needle devicessuch as those described in U.S. Pat. Nos. 4,886,499; 5,190,521;5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662.Intradermal compositions can be administered by devices which limit theeffective penetration length of a needle into the skin, such as thosedescribed in PCT publication WO 99/34850 and functional equivalentsthereof. Jet injection devices which deliver liquid vaccines to thedermis via a liquid jet injector and/or via a needle which pierces thestratum corneum and produces a jet which reaches the dermis aresuitable. Jet injection devices are described, for example, in U.S. Pat.Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil in water and/or water in oil emulsions such as creams,ointments and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations can, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration can further comprise one or more of the additionalingredients described herein.

A pharmaceutically acceptable composition of the invention can beprepared, packaged, and/or sold in a formulation suitable for pulmonaryadministration via the buccal cavity. Such a formulation can comprisedry particles which comprise the active ingredient and which have adiameter in the range from about 0.5 to about 7 nanometers or from about1 to about 6 nanometers. Such compositions are conveniently in the formof dry powders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions caninclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant can constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient can constitute 0.1 to 20% (w/w) of the composition.The propellant can further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which can have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutically acceptable compositions of the invention formulated forpulmonary delivery can provide the active ingredient in the form ofdroplets of a solution and/or suspension. Such formulations can beprepared, packaged, and/or sold as aqueous and/or dilute alcoholicsolutions and/or suspensions, optionally sterile, comprising the activeingredient, and can conveniently be administered using any nebulizationand/or atomization device. Such formulations can further comprise one ormore additional ingredients including, but not limited to, a flavoringagent such as saccharin sodium, a volatile oil, a buffering agent, asurface active agent, and/or a preservative such asmethylhydroxybenzoate. The droplets provided by this route ofadministration can have an average diameter in the range from about 0.1to about 200 nanometers.

The formulations described herein as being useful for pulmonary deliveryare useful for intranasal delivery of a pharmaceutically acceptablecomposition of the invention. Another formulation suitable forintranasal administration is a coarse powder comprising the activeingredient and having an average particle from about 0.2 to 500micrometers. Such a formulation is administered, by rapid inhalationthrough the nasal passage from a container of the powder held close tothe nares.

Formulations suitable for nasal administration can, for example,comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) ofthe active ingredient, and can comprise one or more of the additionalingredients described herein. A pharmaceutically acceptable compositionof the invention can be prepared, packaged, and/or sold in a formulationsuitable for buccal administration. Such formulations can, for example,be in the form of tablets and/or lozenges made using conventionalmethods, and can comprise, for example, 0.1 to 20% (w/w) activeingredient, the balance comprising an orally dissolvable and/ordegradable composition and, optionally, one or more of the additionalingredients described herein. Alternately, formulations suitable forbuccal administration can comprise a powder and/or an aerosolized and/oratomized solution and/or suspension comprising the active ingredient.Such powdered, aerosolized, and/or aerosolized formulations, whendispersed, can have an average particle and/or droplet size in the rangefrom about 0.1 to about 200 nanometers, and can further comprise one ormore of the additional ingredients described herein.

A pharmaceutically acceptable composition of the invention can beprepared, packaged, and/or sold in a formulation suitable for ophthalmicadministration. Such formulations can, for example, be in the form ofeye drops including, for example, a 0.1/1.0% (w/w) solution and/orsuspension of the active ingredient in an aqueous or oily liquidcarrier. Such drops can further comprise buffering agents, salts, and/orone or more other of the additional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are contemplated asbeing within the scope of this invention.

Although the descriptions of pharmaceutically acceptable compositionsprovided herein are principally directed to pharmaceutical compositionswhich are suitable for administration to humans, it will be understoodby the skilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticallyacceptable compositions suitable for administration to humans in orderto render the compositions suitable for administration to variousanimals is well understood, and the ordinarily skilled veterinarypharmacologist can design and/or perform such modification with ordinaryexperimentation.

Also provided are kits comprising one or more compounds of the invention(or pharmaceutically acceptable salts or prodrugs thereof), and/or oneor more pharmaceutically acceptable compositions as described herein.Kits are typically provided in a suitable container (e.g., for example,a foil, plastic, or cardboard package). In certain embodiments, a kitcan include one or more pharmaceutical excipients, pharmaceuticaladditives, therapeutically active agents, and the like, as describedherein. In certain embodiments, a kit can include means for properadministration, such as, for example, graduated cups, syringes, needles,cleaning aids, and the like. In certain embodiments, a kit can includeinstructions for proper administration and/or preparation for properadministration.

Methods of Treatment

Provided are methods for treating an FAAH-mediated disorder byadministering a therapeutically effective amount of a compound of any offormulae I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa, and VIIIb, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, or mixture thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or mixturethereofto a subject in need thereof.

Also provided are methods for inhibiting FAAH in a subject byadministering a therapeutically effective amount of a compound of any offormulae I, II, III, IIIa, IIIb, IV, IVa, IVb, V, VI, VIa, VIb, VII,VIIa, VIIb, VIII, VIIIa, and VIIIb, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, or mixture thereof, to a subject inneed thereof.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, condition, or disorder,which reduces the severity of the disease or disorder, or retards orslows the progression of the disease or disorder. Treatment can be viaprophylactic or therapeutic therapy.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease,disorder, or condition, or to delay or minimize one or more symptomsassociated with the disease, disorder, or condition. A therapeuticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other therapies, which provides atherapeutic benefit in the treatment or management of the disease orcondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of disease, disorder, or condition, or enhances the therapeuticefficacy of another therapeutic agent. The therapeutically effectiveamount in a subject will vary depending on the compound, the disease andits severity, and the age, weight, etc., of the subject to be treated.In some embodiments, a “therapeutically effective amount” can encompassa “prophylactically effective amount.”

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder, or condition, or one or more symptoms associated withthe disease, disorder, or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount oftherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thespecified disease, disorder, or condition in a subject who has alreadysuffered from the disease or disorder, and/or lengthening the time thata subject who has suffered from the disease, disorder, or conditionremains in remission. The terms encompass modulating the threshold,development and/or duration of the disease, disorder or condition, orchanging the way that a subject responds to the disease, disorder, orcondition.

The term “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans (e.g., male,female, infant, child, adolescant, adult, elderly, etc.)), cows, sheep,goats, horses, dogs, cats, birds, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

In other embodiments, the present invention provides a method forinhibiting FAAH in a biological sample comprising the step of contactingsaid sample with a compound of any of formulae I, II, III, IIIa, IIIb,IV, IVa, IVb, V, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb,or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.

The phrases “FAAH-mediated diseases,” “FAAH-mediated disorders” and“FAAH-mediated conditions,” as used interchangeably, include, but arenot limited to, painful conditions, painful diseases or painfuldisorders, inflammatory disorders, immune disorders, depression,anxiety, anxiety-related disorders, sleep disorders, feeding behaviors,movement disorders, glaucoma, neuroprotection and cardiovasculardisease. The terms “disease,” “disorder,” and “condition” are usedinterchangeably.

In certain embodiments, the FAAH-mediated disorder is a painfuldisorder. As used herein, a “painful disorder” includes, but is notlimited to, neuropathic pain (e.g., peripheral neuropathic pain),central pain, deafferentiation pain, chronic pain (e.g., chronicnociceptive pain, and other forms of chronic pain such as post-operativepain), stimulus of nociceptive receptors, acute pain (e.g., phantom andtransient acute pain), non-inflammatory pain, inflammatory pain, painassociated with cancer, wound pain, burn pain, post-operative pain, painassociated with medical procedures, arthritic pain (e.g., painassociated with rheumatoid arthritis, osteoarthritis), lumbosacral pain,musculo-skeletal pain, headache, migraine, muscle ache, lower back andneck pain, toothache and the like.

In certain embodiments, the painful disorder is neuropathic pain. Theterm “neuropathic pain” refers to pain resulting from injury to a nerve.Neuropathic pain is distinguished from nociceptive pain, which is thepain caused by acute tissue injury involving small cutaneous nerves orsmall nerves in muscle or connective tissue. Neuropathic pain typicallyis long-lasting or chronic and often develops days or months followingan initial acute tissue injury. Neuropathic pain can involve persistent,spontaneous pain as well as allodynia, which is a painful response to astimulus that normally is not painful. Neuropathic pain also can becharacterized by hyperalgesia, in which there is an accentuated responseto a painful stimulus that usually is trivial, such as a pin prick.Neuropathic pain conditions can develop following neuronal injury andthe resulting pain may persist for months or years, even after theoriginal injury has healed. Neuronal injury can occur in the peripheralnerves, dorsal roots, spinal cord or certain regions in the brain.Neuropathic pain conditions include: diabetic neuropathy; sciatica;non-specific lower back pain; multiple sclerosis pain; fibromyalgia;HIV-related neuropathy; neuralgia, such as post-herpetic neuralgia andtrigeminal neuralgia; and pain resulting from physical trauma,amputation, cancer, chemotherapy-induced pain, chemotherapy, surgery,invasive medical procedures, toxins burns, infection, or chronicinflammatory conditions. Neuropathic pain can result from a peripheralnerve disorder such as neuroma; nerve compression; nerve crush, nervestretch or incomplete nerve transsection; mononeuropathy orpolyneuropathy. Neuropathic pain can also result from a disorder such asdorsal root ganglion compression; inflammation of the spinal cord;contusion, tumor or hemisection of the spinal cord; tumors of thebrainstem, thalamus or cortex; or trauma to the brainstem, thalamus orcortex.

The symptoms of neuropathic pain are heterogeneous and are oftendescribed as spontaneous shooting and lancinating pain, or ongoing,burning pain. In addition, there is pain associated with normallynon-painful sensations such as “pins and needles” (paraesthesias anddysesthesias), increased sensitivity to touch (hyperesthesia), painfulsensation following innocuous stimulation (dynamic, static or thermalallodynia), increased sensitivity to noxious stimuli (thermal, cold,mechanical hyperalgesia), continuing pain sensation after removal of thestimulation (hyperpathia) or an absence of or deficit in selectivesensory pathways (hypoalgesia).

In certain embodiments, the painful disorder is non-inflammatory painand/or inflammatory pain. The types of non-inflammatory pain include,without limitation, peripheral neuropathic pain (e.g., pain caused by alesion or dysfunction in the peripheral nervous system), central pain(e.g., pain caused by a lesion or dysfunction of the central nervoussystem), deafferentation pain (e.g., pain due to loss of sensory inputto the central nervous system), chronic nociceptive pain (e.g., certaintypes of cancer pain), noxious stimulus of nociceptive receptors (e.g.,pain felt in response to tissue damage or impending tissue damage),phantom pain (e.g., pain felt in a part of the body that no longerexists, such as a limb that has been amputated), pain felt bypsychiatric patients (e.g., pain where no physical cause may exist), andwandering pain (e.g., wherein the pain repeatedly changes location inthe body). In certain embodiments, non-inflammatory pain and/orinflammatory pain are associated with disorders such as inflammatorydiseases (e.g., autoimmune disease).

In certain embodiments, the FAAH-mediated disorder is an inflammatorydisorder. The term “inflammatory disorders” refers to those diseases orconditions that are characterized by signs of pain (dolor, from thegeneration of noxious substances and the stimulation of nerves), heat(calor, from vasodilatation), redness (rubor, from vasodilatation andincreased blood flow), swelling (tumor, from excessive inflow orrestricted outflow of fluid), and/or loss of function (functio laesa,which can be partial or complete, temporary or permanent). Inflammatorydisorders include, without limitation, those affecting the blood vessels(e.g., polyarteritis, temporal arteritis); joints (e.g, arthritis:crystalline, osteo-, psoriatic, reactive, rheumatoid, Reiter'ssyndrome); gastrointestinal tract (e.g, Crohn's disease, ulcerativecolitis); skin (e.g, dermatitis); or multiple organs and tissues (e.g,systemic lupus erythematosus). Inflammatory disorders include, but arenot limited to, inflammation associated with vascular diseases, migraineheadaches, tension headaches, arteritis, thyroiditis, aplastic anemia,Hodgkin's disease, scleroderma, rheumatic fever, type I diabetes,myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, hypersensitivity, conjunctivitis, multiplesclerosis, and ischemia (e.g., myocardial ischemia), and the like. Thecompounds and compositions can be useful for treating neuroinflammationassociated with brain disorders (e.g., Parkinson's disease andAlzheimer's disease) and chronic inflammation associated with cranialradiation injury. The compounds can be useful for treating acuteinflammatory conditions (e.g., conditions resulting from infection) andchronic inflammatory conditions (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds can also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia. Inflammation takes on many forms and includes,but is not limited to, acute, adhesive, atrophic, catarrhal, chronic,cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing,focal, granulomatous, hyperplastic, hypertrophic, interstitial,metastatic, necrotic, obliterative, parenchymatous, plastic, productive,proliferous, pseudomembranous, purulent, sclerosing, seroplastic,serous, simple, specific, subacute, suppurative, toxic, traumatic,and/or ulcerative inflammation.

In certain embodiments, the FAAH-mediated disorder is an immunedisorder. Immune disorders, such as auto-immune disorders, include, butare not limited to, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, degenerative joint diseases suchas osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease,haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateralsclerosis, amylosis, acute painful shoulder, psoriatic, and juvenilearthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin inflammation disorders (e.g., psoriasis,eczema, burns, dermatitis), enuresis, eosinophilic disease,gastrointestinal disorders (e.g., inflammatory bowel disease (IBD),peptic ulcers, regional enteritis, diverticulitis, gastrointestinalbleeding, Crohn's disease, gastritis, diarrhoea, irritable bowelsyndrome and ulcerative colitis), and disorders ameliorated by agastroprokinetic agent (e.g., ileus, postoperative ileus and ileusduring sepsis; gastroesophageal reflux disease (GORD, or its synonymGERD); eosinophilic esophagitis, gastroparesis such as diabeticgastroparesis; food intolerances and food allergies and other functionalbowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiacchest pain (NCCP, including costo-chondritis)).

In certain embodiments, the immune disorder is a gastrointestinaldisorder. In some embodiments, the immune disorder is inflammatory boweldisease (e.g., Crohn's disease and/or ulcerative colitis), pepticulcers, regional enteritis, diverticulitis, gastrointestinal bleeding,Crohn's disease, gastritis, diarrhea, irritable bowel syndrome andulcerative colitis. In other embodiments, the immune disorder isinflammatory bowel disease (IBD).

In certain embodiments, the FAAH-mediated disorder is a skin disorder.In some embodiments, the skin disorder is pruritus (itch), psoriasis,eczema, burns or dermatitis. In certain embodiments, the skin disorderis psoriasis. In certain embodiments, the skin disorder is pruritis.

In certain embodiments, the FAAH-mediated disorder is anxiety.“Anxiety,” as used herein, includes, but is not limited to anxiety andanxiety disorders or conditions, such as, for example, clinical anxiety,panic disorder, agoraphobia, generalized anxiety disorder, specificphobia, social phobia, obsessive-compulsive disorder, acute stressdisorder, and post-traumatic stress disorder; and adjustment disorderswith anxious features, anxiety disorders associated with depression,anxiety disorders due to general medical conditions, andsubstance-induced anxiety disorders. This treatment can also be toinduce or promote sleep in a patient (e.g., for example, a subject withanxiety).

In certain embodiments, the FAAH-mediated disorder is a sleep disorder.“Sleep disorders” include, but are not limited to, insomia, sleep apnea,restless legs syndrome (RLS), delayed sleep phase syndrome (DSPS),periodic limb movement disorder (PLMD), hypopnea syndrome, rapid eyemovement behavior disorder (RBD), shift work sleep disorder (SWSD), andsleep problems (e.g., parasomnias) such as nightmares, night terrors,sleep talking, head banging, snoring, and clenched jaw and/or grindingof teeth (bruxism).

In certain embodiments, the FAAH-mediated disorder is depression.“Depression,” as used herein, includes, but is not limited to,depressive disorders or conditions, such as, for example, majordepressive disorders (unipolar depression), dysthymic disorders(chronic, mild depression) and bipolar disorders (manic-depression). Thedepression can be clinical or subclinical depression.

In certain embodiments, the FAAH-mediated disorder is feeding behavior.“Feeding behavior,” as used herein, includes but is not limited to,eating disorders (e.g., anorexias and cachexias of various natures,over-eating leading to obesity), weight loss associated with cancer,weight loss associated with other general medical conditions, weightloss associated with failure to thrive, and other wasting conditions.The compounds disclosed herein can also be used to reduce body fat andfor treating or preventing obesity in a mammal. The compounds disclosedherein can also be used for preventing or treating the diseasesassociated with these health conditions.

In certain embodiments, the FAAH-mediated disorder is a movementdisorder. In other embodiments, the FAAH-mediated disorder is glaucoma.In yet other embodiments, the FAAH-mediated disorder is neuroprotection.In still yet other embodiments, the FAAH-mediated disorder iscardiovascular disease.

Administration

Provided compounds can be administered using any amount and any route ofadministration effective for treatment. The exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the infection, the particularcomposition, its mode of administration, its mode of activity, and thelike.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease, disorder, or conditionbeing treated and the severity of the disorder; the activity of thespecific active ingredient employed; the specific composition employed;the age, body weight, general health, sex and diet of the subject; thetime of administration, route of administration, and rate of excretionof the specific active ingredient employed; the duration of thetreatment; drugs used in combination or coincidental with the specificactive ingredient employed; and like factors well known in the medicalarts.

The compounds and compositions provided herein can be administered byany route, including oral, intravenous, intramuscular, intra-arterial,intramedullary, intrathecal, subcutaneous, intraventricular,transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical(as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal,enteral, sublingual; by intratracheal instillation, bronchialinstillation, and/or inhalation; and/or as an oral spray, nasal spray,and/or aerosol. Specifically contemplated routes are systemicintravenous injection, regional administration via blood and/or lymphsupply, and/or direct administration to an affected site. In general themost appropriate route of administration will depend upon a variety offactors including the nature of the agent (e.g., its stability in theenvironment of the gastrointestinal tract), the condition of the subject(e.g., whether the subject is able to tolerate oral administration),etc.

The exact amount of a compound required to achieve a therapeuticallyeffective amount will vary from subject to subject, depending, forexample, on species, age, and general condition of a subject, severityof the side effects or disorder, identity of the particular compound(s),mode of administration, and the like. The desired dosage can bedelivered three times a day, two times a day, once a day, every otherday, every third day, every week, every two weeks, every three weeks, orevery four weeks. In certain embodiments, the desired dosage can bedelivered using multiple administrations (e.g., two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, ormore administrations).

In certain embodiments, a therapeutically effective amount of a compoundfor administration one or more times a day to a 70 kg adult human cancomprise about 0.0001 mg to about 1000 mg of an inventive compound perunit dosage form. For example, a therapeutically effective amount of acompound of the present invention can comprise about 0.01 mg, about 0.5mg, about 1 mg, about 2, mg, about 3 mg, about 5 mg, about 10 mg, about25 mg, about 50 mg, about 70 mg, about 100 mg, about 200 mg, about 300mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800mg, about 900 mg, or about 1000 mg depending on the compound, thedisease and its severity, and the age, weight, etc., of the subject tobe treated. It will be appreciated that dose ranges as described hereinprovide guidance for the administration of provided pharmaceuticallyacceptable compositions to an adult. The amount to be administered to,for example, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the sameas that administered to an adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionaltherapeutically active agents. The compound or composition can beadministered concurrently with, prior to, or subsequent to, one or moreadditional therapeutically active agents. In general, each agent will beadministered at a dose and/or on a time schedule determined for thatagent. In will further be appreciated that the additionaltherapeutically active agent utilized in this combination can beadministered together in a single composition or administered separatelyin different compositions. The particular combination to employ in aregimen will take into account compatibility of the inventive compoundwith the additional therapeutically active agent and/or the desiredtherapeutic effect to be achieved. In general, it is expected thatadditional therapeutically active agents utilized in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually.

The compounds or compositions can be administered in combination withagents that improve their bioavailability, reduce and/or modify theirmetabolism, inhibit their excretion, and/or modify their distributionwithin the body. It will also be appreciated that therapy employed canachieve a desired effect for the same disorder (for example, a compoundcan be administered in combination with an anti-inflammatory,anti-anxiety and/or anti-depressive agent, etc.), and/or it can achievedifferent effects (e.g., control of adverse side-effects).

Exemplary active agents include, but are not limited to, anti-canceragents, antibiotics, anti-viral agents, anesthetics, anti-coagulants,inhibitors of an enzyme, steroidal agents, steroidal or non-steroidalanti-inflammatory agents, antihistamine, immunosuppressant agents,anti-neoplastic agents, antigens, vaccines, antibodies, decongestants,sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics,hormones, prostaglandins, progestational agents, anti-glaucoma agents,ophthalmic agents, anti-cholinergics, anti-depressants, anti-psychotics,hypnotics, tranquilizers, anti-convulsants, muscle relaxants,anti-spasmodics, muscle contractants, channel blockers, miotic agents,anti-secretory agents, anti-thrombotic agents, anticoagulants,anti-cholinergics, β-adrenergic blocking agents, diuretics,cardiovascular active agents, vasoactive agents, vasodilating agents,anti-hypertensive agents, angiogenic agents, modulators ofcell-extracellular matrix interactions (e.g. cell growth inhibitors andanti-adhesion molecules), or inhibitors/intercalators of DNA, RNA,protein-protein interactions, protein-receptor interactions, etc. Activeagents include small organic molecules such as drug compounds (e.g.,compounds approved by the Food and Drugs Administration as provided inthe Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins and cells.

In certain embodiments, the additional therapeutically active agent is apain-relieving agent. In other embodiments, the additionaltherapeutically active agent is an anti-inflammatory agent.

Methods of Determining Biological Activity

Methods of determining the activity of the compounds provided herein forvarious therapeutic uses are known in the art. These include, but arenot limited to, high throughput screening to identify compounds thatbind to and/or modulate the activity of isolated FAAH, as well as invitro and in vivo models of therapies.

Assays useful for screening the compounds provided herein can detect thebinding of the inhibitor to FAAH or the release of a reaction product(e.g., fatty acid amide or ethanolamine) produced by the hydrolysis of asubstrate such as oleoylethanolamide or ananadamide. The substrate canbe labeled to facilitate detection of the released reaction products.U.S. Pat. No. 5,559,410 discloses high throughput screening methods forproteins, and U.S. Pat. Nos. 5,576,220 and 5,541,061 disclose highthroughput methods of screening for ligand/antibody binding.

Methods for screening FAAH inhibitors for an antinociceptive effect areknown in the art. For example, compounds can tested in the mousehot-plate test and the mouse formalin test, and the nociceptivereactions to thermal or chemical tissue damage measured (for example,see U.S. Pat. No. 6,326,156 for a description of methods of screeningfor antinociceptive activity; see also Cravatt et al. Proc. Natl. Acad.Sci. U.S.A. (2001) 98:9371-9376).

Two pharmacologically validated animal models of anxiety are theelevated zero maze test, and the isolation-induced ultrasonic emissiontest. The zero maze consists of an elevated annular platform with twoopen and two closed quadrants and is based on the conflict between ananimal's instinct to explore its environment and its fear of open spaces(see, for example, Bickerdike, M. J. et al., Eur. J. Pharmacol., (994)271, 403-411; Shepherd, J. K. et al., Psychopharmacology, (1994) 116,56-64). Clinically used anxiolytic drugs, such as the benzodiazepines,increase the proportion of time spent in, and the number of entries madeinto, the open compartments.

A second test for an anti-anxiety compound is the ultrasonicvocalization emission model, which measures the number of stress-inducedvocalizations emitted by rat pups removed from their nest (see, forexample, Insel, T. R. et al., Pharmacol. Biochem. Behav., 24, 1263-1267(1986); Miczek, K. A. et al., Psychopharmacology, 121, 38-56 (1995);Winslow, J. T. et al., Biol. Psychiatry, 15, 745-757 (1991).

The effect of the compounds provided herein in the treatment ofdepression can be tested in the model of chronic mild stress inducedanhedonia in rats. This model is based on the observation that chronicmild stress causes a gradual decrease in sensitivity to rewards, forexample consumption of sucrose, and that this decrease isdose-dependently reversed by chronic treatment with antidepressants.See, e.g., Willner, Paul, Psychopharmacology, 1997, 134, 319-329.

Another test for antidepressant activity is the forced swimming test(Nature 266, 730-732, 1977). In this test, animals are administered anagent 30 or 60 minutes before being placed in container of water, andthe time during which they remain immobile is recorded. A decrease inthe immobility time of the mice is indicative of antidepressantactivity.

A similar test for antidepressant activity is the mouse caudalsuspension test (Psychopharmacology, 85, 367-370, 1985). In this test,animals are administered an agent 30 or 60 minutes before beingsuspended by the tail, and their immobility time is recorded. A decreasein the immobility time of the mice is indicative of antidepressantactivity.

Animal models are available for assessing anticonvulsant activity oftest compounds (see, e.g., U.S. Pat. Nos. 6,309,406 and 6,326,156).

Inhibition of FAAH has been reported to induce sleep in test animals(see, e.g., U.S. Pat. No. 6,096,784). Methods for studying sleepinducing compounds are known in the art (see, e.g., U.S. Pat. Nos.6,096,784 and 6,271,015). Compounds can be administered to a test animal(e.g., rat or mouse) or a human and the subsequent time (e.g., onset,duration) spent sleeping (e.g., eyes closed, motor quiescence) can bemonitored. See also WO 98/24396.

Methods for screening FAAH inhibitors which induce catalepsy are alsowell known in the art (see, e.g., Quistand et al. in Toxicology andApplied Pharmacology 173: 48-55 (2001); Cravatt et al. Proc. Natl. Acad.Sci. U.S.A. 98:9371-9376 (2001)).

Methods of assessing appetitive behavior are known in the art (see,e.g., U.S. Pat. No. 6,344,474). One method of assessing the effect onappetite behavior is to administer a FAAH inhibitor to a rat and assessits effect on the intake of a sucrose solution (see, e.g., W. C. Lynchet al., Physiol. Behav., 1993, 54, 877-880).

Methods of Synthesis

The reaction of an organometallic species with an organic borate, suchas trimethyl borate, can be used to synthesize boronate esters. Suitableorganometallic species include, but are not limited to, alkyl lithiumand Grignard reagents. Other methods for the synthesis of boronates areemployed when the boronate contains sensitive functionality that may nottolerate alkyl lithium reagents or Grignard reagents. These methodsinclude palladium coupling reactions of aryl or akenyl halides anddiboronates or dialkoxy boranes and hydroboration of alkenes or alkynes.Using these methods a diverse collection of boronates can besynthesized. Boronates can be readily transformed in to boronic acids byhydrolyzing the boronate under aqueous acidic conditions using asuitable acid. Suitable acids include, but are not limited to HCl,H₂SO₄, and HBr. Another method of hydrolyzing boronates is an oxidativehydrolysis employing an oxidizing agent, such as NaIO₄. The boronic acidcompounds of the present invention readily form boronic esters whenexposed to alcohols. The resulting boronic esters can also be used inthe methods provided herein. Cyclic boronates are formed when certaindiols (e.g., 1,2- and 1,3-diols) are used. Boronic acid compoundsprovided herein readily form oligomeric anhydrides by dehydration of theboronic acid moiety to form dimers, trimers, and tetramers, and mixturesthereof. These species in the presence of water and under physiologicalconditions convert back to the boronic acid by hydrolysis.

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

General Synthetic Methods

The following is a description of general synthetic routes that can beused to prepare compounds of the present invention. Additionally, one ofskill in the art will recognize that protecting groups may be necessaryfor the preparation of certain compounds and will be aware of thoseconditions compatible with a selected protecting group. Examples of suchprotecting groups include, for example, those set forth in ProtectiveGroups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley &Sons, New York, N.Y., (3rd Edition, 1999). Accordingly, the exemplarymethods and the examples described herein are illustrative of thepresent invention and are not to be construed as limiting the scopethereof.

Method 1:

General conditions for the conversion of boronate esters to boronicacids: The boronate ester (1.0 eq), sodium periodate (5.0 eq) andammonium acetate (5.0 eq) are dissolved in acetone/water 2:1 (0.05 Mboronate ester) and stirred for 12 hours at 23° C. until TLC or LCMSindicated conversion to the boronic acid is complete. One option forisolation is to precipitate the product by dilution of the mixture with1N aqueous HCl and collection of the solid boronic acid by filtration.Alternately, the mixture is partitioned between water and ethyl acetate,and the organic layer washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The residue is purified either byrecrystallization and trituration (heptane, acetonitrile, or othersolvents) or by flash silica gel chromatography (0.5% to 10%methanol/dichloromethane) to afford pure boronic acid.

Method 2:

General conditions for the conversion of boronate esters to boronicacids: The boronate ester (1.0 eq), and sodium periodate (3.0 eq) aredissolved in acetone/water 2:1 (0.05 M boronate ester) after which point1N HCl (1.5 eq) is added and the reaction is stirred for 12 h at 23° C.until TLC or LCMS indicated conversion to the boronic acid is complete.One option for isolation is to precipitate the product by dilution ofthe mixture with additional 1N aqueous HCl and collection of the solidboronic acid by filtration. Alternately, the mixture can be partitionedbetween water and ethyl acetate, and the organic layer washed withbrine, dried over sodium sulfate, and concentrated in vacuo. The residueis purified either by recrystallization and trituration (heptane,acetonitrile, or other solvents) or by flash silica gel chromatography(0.5% to 10% methanol/dichloromethane) to afford pure boronic acid.

Method 3:

General conditions for the deprotection of a N-Boc carbamate in thepresence of a boronate ester: The boronate ester is dissolved intert-butylmethylether (0.4 M final ester concentration) after whichpoint HCl (g) is bubbled in over the course of 15 min. The reaction isallowed to stir at room temperature for an additional hour after whichpoint the solvent is removed under a stream of nitrogen to provide thedesired HCl amine salt as a white solid in quantitative yield.

Method 4:

General conditions for the reduction of tetrahydropyridines topiperidines in the presence of a boronate ester: The boronate ester isdissolved in ethyl acetate/methanol (1:1 v/v) (0.4 M final esterconcentration) after which Pd(OH)₂ (0.35 equiv) is added and thereaction is allowed to stir under an atmosphere of H₂ for 14 h. At thispoint the reaction is filtered through and concentrated in vacuo toprovide the desired piperidine in quantitative yield.

EXAMPLES

Exemplary compounds are set forth in the Examples provided below.Compounds were assayed as inhibitors of human FAAH using the methoddescribed in detail in Example 19. Activity designated as “A” refers tocompounds having a K_(i) of less than or equal to 0.01 μM, “B” refers tocompounds having a K_(i) of between 0.01 μM and 0.1 μM, “C” refers tocompounds having a K_(i) of between 0.1 μM and 1 μM, and “D” refers tocompounds having a K_(i) of greater than 1 μM.

Example 1

Tetrahydropyridine 1 was prepared in 1 step from commercially available4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateusing Method 1 and was isolated after precipitation from the reactionmixture. [M-H]−=226.1 m/z. Activity: C

Example 2

Tetrahydropyridine 2 was prepared in 3 steps starting with thedeprotection of 1 using Method 3. The resulting HCl amine salt wasdissolved in dichloromethane (0.2 M). Benzyl chloroformate (1.2 equiv)was added followed by triethylamine (3.0 equiv). The reaction wasallowed to stir at room temperature for 2 h after which point it wasdiluted with 1N HCl and extracted with excess dichloromethane. Theorganic layer was dried over MgSO₄ and concentrated to provide thedesired carbamate in quantitative yield, which was converted directly toboronic acid 2 using Method 2. [M-H]−=260.1 m/z. Activity: B

Example 3

Tetrahydropyridine 3 was prepared as described in Example 2, except thatacetyl chloride was used in place of benzyl chloroformate. Activity: D

Example 4

Tetrahydropyridine 4 was prepared as described in Example 2, except that4-chlorobenzoyl chloride was used in place of benzyl chloroformate.Activity: B

Example 5

Tetrahydropyridine 5 was prepared in 2 steps starting with thedeprotection of 1 using Method 3. The resulting HCl amine salt wasdissolved in N,N-dimethylformamide (0.2 M).3-Methyl-1-benzothiophene-2-carboxylic acid (1.0 equiv) and PyBOP (1.0equiv) were added followed by the dropwise addition of triethylamine(3.0 equiv). After stirring at room temperature for 30 min, the reactionwas diluted with water and filtered. The isolated material was thenpurified using semi-preparatory liquid chromatography to isolate thefraction of desired boronic acid 5 that resulted from pinacol esterdeprotection during the course of the acid coupling. [M-H]−=300.1 m/z.Activity: B

Example 6

Tetrahydropyridine 6 was prepared as described in Example 5 except that(3-methyl-1-benzothien-2-yl)acetic acid was used in place of3-methyl-1-benzothiophene-2-carboxylic acid. Activity: B

Example 7

Tetrahydropyridine 7 was prepared in 3 steps starting with thedeprotection of 1 using Method 3. The resulting HCl amine salt wassuspended in dichloromethane (0.2 M). Triphosgene (0.67 equiv) was addedfollowed by benzylamine (2.67 equiv) and triethylamine (5.0 equiv) afterwhich point the reaction became homogeneous. The reaction was allowed tostir at room temperature for 2 h after which point it was diluted with1N HCl and extracted with excess dichloromethane. The organic layer wasdried over MgSO₄, and concentrated to provide the desired urea which wasconverted directly to boronic acid 7 using Method 2 and isolated usingsemi-preparatory reverse phase liquid chromatography. [M-H]−=259.1 m/z.Activity: B

Example 8

Piperidine 8 was prepared in 2 steps from compound 1 using Method 4followed by pinacol ester deprotection using Method 2. [M-H]−=228.2 m/z.Activity: B

Example 9

Piperidine 9 was prepared in 4 steps from compound 1 using Method 4followed by Boc deprotection using Method 3. The resulting amine HClsalt was treated with benzyl chloroformate using the same conditions asin Example 2 followed by pinacol ester deprotection using Method 2.[M-H]−=262.1 m/z. Activity: B

Example 10

Piperidine 10 was prepared in 4 steps from compound 1 using Method 4followed by Boc deprotection using Method 3. The resulting amine HClsalt was treated with 5-phenylpropionic acid using the couplingconditions outlined in Example 5 followed by pinacol ester deprotectionusing Method 2. The product was isolated using semi-preparatory reversephase liquid chromatography. [M-H]−=288.2 m/z. Activity: B

Example 11

Piperidine 11 was prepared in 4 steps from compound 1 using Method 4followed by Boc deprotection using Method 3. The resulting amine HClsalt was treated with 4-chlorobenzoyl chloride using the couplingconditions outlined in Example 2. The product was isolated using flashsilica gel chromatography (gradient of hexanes/ethyl acetate). Thedesired boronic acid was isolated using semi-preparatory reverse phaseliquid chromatography followed by pinacol ester deprotection usingMethod 2. [M-H]−=266.1 m/z. Activity: C

Example 12

Piperidine 12 was prepared in 4 steps from compound 1 using Method 4followed by Boc deprotection using Method 3. The resulting amine HClsalt was treated with quinoline-3-carboxylic acid using the couplingconditions outlined in Example 5. The desired boronic acid was isolatedusing semi-preparatory reverse phase liquid chromatography followed bypinacol ester deprotection using Method 2. [M-H]−=288.2 m/z. Activity: C

Example 13

Piperidine 13 was prepared in 4 steps from compound 1 using Method 4followed by Boc deprotection using Method 3. The resulting amine HClsalt was treated with quinaldic acid using the coupling conditionsoutlined in Example 5. The desired boronic acid was isolated usingsemi-preparatory reverse phase liquid chromatography followed by pinacolester deprotection using Method 2. [M-H]−=288.2 m/z. Activity: C

Example 14

Piperidine 14 was prepared in 3 steps from compound 1 using Method 4followed by Boc deprotection using Method 3. The resulting amine HClsalt was treated with N-benzylglycine using the coupling conditionsoutlined in Example 5 to provide a mixture of pinacol ester boronate andthe desired boronic acid 14 which was isolated using semi-preparatoryreverse phase liquid chromatography. [M-H]−=275.2 m/z. Activity: D

Example 15

Piperidine 15 was prepared in 3 steps from compound 1 using Method 4followed by Boc deprotection using Method 3. The resulting amine HClsalt was treated with L-proline using the coupling conditions outlinedin Example 5 to provide a mixture of Boc-deprotected pinacol esterboronate and the desired boronic acid 15 which was isolated usingsemi-preparatory reverse phase liquid chromatography. [M-H]−=225.1 m/z.Activity: D

Example 16

Piperidine 16 was prepared in 4 steps from compound 1 using Method 4followed by Boc deprotection using Method 3. The resulting amine HClsalt was treated with 4-methylbenzene sulfonyl chloride using the sameconditions outlined in Example 2 followed by pinacol ester deprotectionusing Method 2. [M-H]−=282.1 m/z. Activity: C

Example 17

Piperidine 17 was prepared in 4 steps from compound 1 using Method 4followed by Boc deprotection using Method 3. The resulting amine HClsalt was suspended in methylene chloride (0.2 M) and benzyl bromide (3.0equiv) was added followed by the addition of triethylamine (1.0 equiv).The reaction was allowed to stir at room temperature for 14 h afterwhich point it was diluted with 1N HCl and extracted with excess diethylether/hexane (1:1 v/v). The aqueous layer was then basified with NaHCO₃and extracted with ethyl acetate. The organic layer was dried over MgSO₄and concentrated to provide the desired tertiary amine, which wasconverted directly to boronic acid 17 using Method 2 and isolated usingsemi-preparatory reverse phase liquid chromatography. [M-H]−=218.1 m/z.Activity: D

Example 18

(3-Methyl-1-benzothien-2-yl)methanol was dissolved in methylene chloride(0.2 M). Methane sulfonyl chloride (1.1 equiv) was added followed bytriethylamine (1.1 equiv) and the reaction was allowed to stir overnightat room temperature after which point it was diluted with 1N HCl andextracted with excess dichloromethane. The organic layer was dried overMgSO₄, and concentrated to provide the desired mesyl alcohol inquantitative yield. This mesyl alcohol (1.3 equiv) was added to asuspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidienhydrochloride (formed from compound 1 using Method 4 followed by Bocdeprotection using Method 3) followed by the addition of triethylamine(4.0 equiv). The reaction was allowed to stir overnight at roomtemperature after which point it was diluted with 1N HCl and extractedwith excess dichloromethane. The organic layer was dried over MgSO₄, andconcentrated to provide a mixture of pinacol ester boronate and thedesired boronic acid 18 which was isolated using semi-preparatoryreverse phase liquid chromatography. [M-H]−=288.1 m/z. Activity: B

Example 19 Inhibition of Rat and Human FAAH

The following assays can be used to determine the inhibition of FAAH:(1) a fluorescence-based assay (Manjunath et al., AnalyticalBiochemistry (2005) 343:143-151); and (2) a microsome-based fluorescentassay (Wang et al., Biomolecular Screening (2006) 1-9).

Rat FAAH Preparation:

Five rat livers were homogenized in five fold volume with ice cold Tris(20 mM pH 8.0) and 0.32 M Sucrose solution via an Ultra Turrax T25homogenizer. All subsequent preparation steps were carried out at 4° C.The homogenate was centrifuged at 6000 g, for 20 minutes and the pellet,containing nuclear debris and mitochondria was discarded. Thesupernatant was centrifuged at 40,000 g for 30 minutes. The supernatantwas discarded and the pellet solubilized via a dounce homogenizer inresuspension buffer (20 mM Hepes pH 7.8, 10% v/v glycerol, 1 mM EDTA, 1%triton X-100) overnight at 4° C. to resolubilize membrane bound FAAH.The solution was centrifuged at 40,000 g for 30 minutes and the pelletdiscarded. The supernatant containing rat FAAH was aliquoted and flashfrozen with liquid nitrogen and stored for long term usage at −80° C.

Human FAAH Preparation:

COS-7 cells were split the day before, 1:5 into 150 mm×25 mm cellculture dishes (Corning Inc., Cat. No. 430599). Transient transfectiontook place at 30-40% confluency according to FuGENE 6 TransfectionReagent (Roche, Cat. No. 11814 443 001).

Transfection Procedure:

The FuGENE transfection 6 reagent (45 uL) was added to 1410 μL of media(DMEM, serum free without pen/strep) in a 15 mL conical tube andincubated at room temp for 5 minutes, followed by the addition of FAAHplasmid DNA (15 ng) (OriGene Cat. No. TC119221, Genbank Accession No.NM_(—)001441.1, 0.67 ug/uL) and a further incubation of 15 minutes atroom temperature. The resulting solution was added into one dish of30-40% confluent COS-7 cells in a drop-wise manner. The COS-7 cell dishwas subsequently incubated for 48 hours. The cells were then harvested.

Harvest Procedure:

Media was aspirated from the dishes and the cells rinsed with 10 mL PBS.The PBS was removed and 3 mL of PBS added to the dish. The dish wasscraped to resuspend the cells, and the subsequent cell suspensioncollected into a 15 mL conical tube. The cells were pelleted bycentrifugation at 1200 rpm for 5 minutes in a bench top centrifuge. PBSwas removed and the cell pellet snap frozen in liquid nitrogen andstored at −80° C.

COS-7 Cells—FAAH Purification:

-   -   (1) Fractionation: Frozen cell pellets from transient        transfections were thawed on ice and resuspended in 12.5 mM        Hepes pH 8.0, 100 mM NaCl, 1 mM EDTA (10 mL/0.2 g cell pellet).        The pellets were dounce homogenized and then sonicated to        produce cell extract. The cell extract was subsequently        centrifuged at 1000 g to remove cellular debris. The pellet was        discarded and the supernatant centrifuged at 13,000 g for 20        minutes. The pellet contained membrane bound FAAH. The        supernatant was discarded and the pellet resolubilized.    -   (2) Re-solubilization: The fraction of interest, (13,000 g,        membrane fraction) was re-suspended in 2.3 mL re-suspension        buffer (20 mM Hepes pH 7.8, 10% v/v Glycerol, 1 mM EDTA, 1%        Triton X-100) and the sample incubated on ice for 1 hour and        then centrifuged to remove any particulate matter. The        supernatant containing solubilized human FAAH was aliquoted and        snap frozen in liquid nitrogen and stored at −80° C. until use.    -   (3) Characterization: Protein Concentration determined by        Bradford assay.        -   SDS gel and Western blot to confirm presence of FAAH        -   FAAH activity assay        -   Km determination—96-well assay        -   Linear dependence—96-well assay        -   Standard compound Ki determination—384-well assay

Rat FAAH Biochemical Inhibition Assay; Materials and Methods:

Rat FAAH biochemical assays were carried out in a 96 well flat bottomblack non-treated polystyrene plates (Corning Costar Catalogue #3915).FAAH reaction buffer: 50 mM Hepes (pH 7.5), 1 mM EDTA, 0.2% TritonX-100. FAAH substrate-AMC Arachidonoyl Amide (Cayman Chemicals Company,Catalog #10005098). The reaction was read in an Envision microtiterplate reader [Excitation filter 355 nm (40 nm bandpass); Emission filter460 nm (25 nm bandpass)]. The raw fluorescence was plotted on the y axisand the inhibitor concentration on the x axis to give a dose responseinhibition curve. The data was fitted to a single site competitiveinhibition equation, fixing the Km for the rat and human enzyme to 12 μMand 9 μM respectively.

Rat FAAH Biochemical Inhibition Assay; Experimental Protocol:

The principle of this assay was the hydrolysis of AMC-Arichodonoyl, afluorescent analogue of Anandamide, which results in the formation ofArachidonic acid and AMC. The formation of AMC results in an increase influorescence (see, for example, Manjunath et al., AnalyticalBiochemistry (2005) 343:143-151; and Wang et al., Biomolecular Screening(2006) 1-9). The inhibition of product formation and hence fluorescenceas a function of inhibitor concentration enables the determination of Kifor the compounds.

A 0.49 mg/ml Rat liver FAAH solution was made up in FAAH reactionbuffer, and 78 ul pipetted into a 96 well plate. To this was added 2 uLof a 3 fold serially diluted inhibitor from a DMSO stock solution. TheFAAH solution and inhibitor were incubated for 30 minutes at roomtemperature. The FAAH reaction was initiated by the addition of 80 μL of40 μM AMC Arachidonoyl Amide in FAAH reaction buffer, yielding a finalreaction FAAH rat liver preparation concentration of 0.25 mg/mL andAMC-Arachidonoyl substrate concentration of 20 μM, reaction volume 160μL. The reaction was allowed to proceed for 4 hours at room temperature.The reaction was stopped by the addition of 80 μL 12 uMa-ketoheterocycle (Cayman Chemicals, catalogue #10435). The microtiterplate was read in the envision plate reader.

Human FAAH Assay; Experimental Protocol:

A 0.1 mg/mL Human FAAH solution was made up in FAAH reaction buffer, and24 ul pipeted into a 384 well plate. To this was added 1 μL of a 3 foldserially diluted inhibitor from a DMSO stock solution. The FAAH solutionand inhibitor were incubated for 30 minutes at room temperature. TheFAAH reaction was initiated by the addition of 25 μL of 40 μM AMCArachidonoyl Amide in FAAH reaction buffer, yielding a final reactionhuman FAAH preparation concentration of 0.05 mg/ml and AMC-Arachidonoylsubstrate concentration of 20 μM, reaction volume 50 μL. The reactionwas allowed to proceed for 4 hours at room temperature. The reaction wasstopped by the addition of 25 μL 12 μM a-ketoheterocycle (CaymanChemicals, catalogue #10435). The microtiter plate was read in theenvision plate reader.

The raw fluorescence was plotted on the y axis and the inhibitorconcentration on the x axis to give a dose response inhibition curve.The data was fitted to a single site competitive inhibition equation,fixing the Km for the rat and human enzyme to 12 μM and 9 μMrespectively.

The contents of all references, pending patent applications andpublished patent applications, cited throughout this application arehereby incorporated by reference in their entirety as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A compound of formula III:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof, wherein:

is selected from a single bond and a double bond; m is 1 when

is a single bond; m is 0 when

is a double bond; Z¹ is —OR¹⁴; Z² is —OR¹⁵; R¹, R², R³, R⁴, R⁶, R⁷, R¹²and R¹³ each independently is selected from H, halogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ perhaloalkyl, —CN, —OR¹⁶, NR¹⁷R¹⁸, —C(O)R¹⁹,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂ aralkyl, 3-10 memberedcycloheteroalkyl, and 5-10 membered heteroaryl; R⁸ is selected from C₂₋₆alkenyl, C₂₋₆ alkynyl, —C(O)R²⁰, —C(O)NR²²R²³, S(O)₂R²⁴, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered cycloheteroalkyl, 5-10 memberedheteroaryl, and —(CH₂)_(p)—R²⁵; R¹⁴ and R¹⁵, at each occurrence, eachindependently is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; R¹⁶, at each occurrence, each independently is selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,C₇₋₁₂ aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 memberedheteroaryl; R¹⁷ and R¹⁸, at each occurrence, each independently isselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —C(O)R²⁶,—C(O)OR²⁷, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂ aralkyl, 3-10 memberedcycloheteroalkyl, and 5-10 membered heteroaryl; R¹⁹, at each occurrence,each independently is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂ aralkyl, 3-10 memberedcycloheteroalkyl, and 5-10 membered heteroaryl; R²⁰ is selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered cycloheteroalkyl, 5-10 membered heteroaryl, and—(CH₂)_(q)—R²⁸; R²² and R²³ each independently is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10membered cycloheteroalkyl, 5-10 membered heteroaryl, and —(CH₂)_(r)—R²⁹;R²⁴ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered cycloheteroalkyl, 5-10 memberedheteroaryl, and —(CH₂)_(t)—R³⁰; R²⁵ is selected from C₃₋₁₀ carbocyclyl,C₆₋₁₀ aryl, 3-10 membered cycloheteroalkyl, and 5-10 memberedheteroaryl; R²⁶ and R²⁷ each independently is selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;R²⁸, R²⁹, and R³⁰, at each occurrence, each independently is selectedfrom —OR³¹, —NR³²R³³, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 memberedcycloheteroalkyl, and 5-10 membered heteroaryl; R³¹, R³² and R³³, ateach occurrence, each independently is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, C₇₋₁₂ aralkyl,3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl; and p, q,r, and t, at each occurrence, each independently is selected from 1, 2,3, 4, 5 and
 6. 2. The compound of claim 1, wherein R⁸ is selected from—C(O)R²⁰, —C(O)NR²²R²³, S(O)₂R₂₄, and —(CH₂)_(p)—R²⁵.
 3. The compound ofclaim 1, wherein R⁸ is —C(O)R²⁰, and R²⁰ is selected from C₁₋₆ alkyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered cycloheteroalkyl, 5-10membered heteroaryl, and —(CH₂)_(q)—R²⁸.
 4. The compound of claim 3,wherein R²⁰ is —(CH₂)_(q)—R²⁸, and R²⁸ is selected from C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered cycloheteroalkyl, and 5-10membered heteroaryl.
 5. The compound of claim 3, wherein R²⁰ is—(CH₂)_(q)—R²⁸, and R²⁸ is —NR³²R³³.
 6. The compound of claim 5, whereinR³² and R¹³ each independently is selected from H, C₁₋₆ alkyl, and C₇₋₁₂aralkyl.
 7. The compound of claim 1, wherein R⁸ is —C(O)NR²²R²³.
 8. Thecompound of claim 7, wherein R²² and R²³ each independently is selectedfrom H, C₁₋₆ alkyl, and —(CH₂)_(r)—R²⁹.
 9. The compound of claim 8wherein R²⁹ is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl.10. The compound of claim 1, wherein R⁸ is —S(O)₂R²⁴.
 11. The compoundof claim 10, wherein R²⁴ is selected from C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and —(CH₂)_(t)—R³⁰.
 12. The compound of claim 1,wherein R⁸ is —(CH₂)_(p)—R²⁵.
 13. The compound of claim 12, wherein R²⁵is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl.
 14. Thecompound of claim 1, wherein R¹² is H and R¹³ is H.
 15. The compound ofclaim 1, wherein R⁶ is H and R⁷ is H.
 16. The compound of claim 1,wherein

is a double bond and m is
 0. 17. The compound of claim 1, wherein

is a single bond and m is
 1. 18. The compound of claim 17, wherein R² isH.
 19. The compound of claim 1, wherein R¹ is H.
 20. The compound ofclaim 1, wherein R³ is H and R⁴ is H.
 21. The compound of claim 1,wherein R¹⁴ is H and R¹⁵ is H.
 22. The compound of claim 1, wherein thecompound is selected from:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.
 23. A pharmaceutical composition comprising a compoundof claim 1 or a pharmaceutically acceptable salt, solvate or prodrugthereof, or mixture thereof and a pharmaceutically acceptable excipient.24. The compound of claim 1, wherein the compound is of the formulaIIIa:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.
 25. The compound of claim 1, wherein the compound is ofthe formula IIIb:

or a pharmaceutically acceptable salt, solvate or prodrug thereof, ormixture thereof.